Journal articles: 'Cytochrome P450 enzyme system'

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Marchenko, M. M., G. P. Kopylchuk, and O. V. Ketsa. "Low doses x-ray irradiation influence on liver detoxication system in rats with transplanted guerin's carcinoma." Biomeditsinskaya Khimiya 56, no. 2 (2010): 266–73. http://dx.doi.org/10.18097/pbmc20105602266.

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The activity of detoxication enzymes in liver microsomal fraction of preliminary radiation-exposed rats was investigated. It was shown that preliminary organism exposure to radiation reduced cytochrome Р450 and glutathione-S-transferase activity in liver microsomal fraction in the latent and logarithmic phases of oncogenesis compared with the unirradiated rats with tumor.Low level of cytochrome Р450 activity can be caused by transition of microsomal cytochrome P450 in P420 inactive form.The preliminary radiation does not influence the enzyme activity of liver cytochrome P450 and glutathione-S-transferase on terminal stages of Guerin's carcinoma growth.

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Correia, Maria Almira, Sheila Sadeghi, and Eduardo Mundo-Paredes. "CYTOCHROME P450 UBIQUITINATION: Branding for the Proteolytic Slaughter?" Annual Review of Pharmacology and Toxicology 45, no. 1 (September 22, 2005): 439–64. http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100127.

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The hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins engaged in the enzymatic oxidation of a wide variety of endo- and xenobiotics. In the course of these reactions, the enzymes generate reactive O2 species and/or reactive metabolic products that can attack the P450 heme and/or protein moiety and structurally and functionally damage the enzyme. The in vivo conformational unraveling of such a structurally damaged P450 signals its rapid removal via the cellular sanitation system responsible for the proteolytic disposal of structurally aberrant, abnormal, and/or otherwise malformed proteins. A key player in this process is the ubiquitin (Ub)-dependent 26S proteasome system. Accordingly, the structurally deformed P450 protein is first branded for recognition and proteolytic removal by the 26S proteasome with an enzymatically incorporated polyUb tag. P450s of the 3A subfamily such as the major human liver enzyme CYP3A4 are notorious targets for this process, and they represent excellent prototypes for the understanding of integral ER protein ubiquitination. Not all the participants in hepatic CYP3A ubiquitination and subsequent proteolytic degradation have been identified. The following discussion thus addresses the various known and plausible events and/or cellular participants involved in this multienzymatic P450 ubiquitination cascade, on the basis of our current knowledge of other eukaryotic models. In addition, because the detection of ubiquitinated P450s is technically challenging, the critical importance of appropriate methodology is also discussed.

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Li, Zhong, Yuanyuan Jiang, F. Peter Guengerich, Li Ma, Shengying Li, and Wei Zhang. "Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications." Journal of Biological Chemistry 295, no. 3 (December 6, 2019): 833–49. http://dx.doi.org/10.1074/jbc.rev119.008758.

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Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics, steroid biosynthesis, and drug metabolism. P450s are considered as the most versatile biocatalysts in nature because of the vast variety of substrate structures and the types of reactions they catalyze. In particular, P450s can catalyze regio- and stereoselective oxidations of nonactivated C–H bonds in complex organic molecules under mild conditions, making P450s useful biocatalysts in the production of commodity pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances. Major efforts have been made in engineering improved P450 systems that overcome the inherent limitations of the native enzymes. In this review, we focus on recent progress of different strategies, including protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, in efforts to more efficiently produce pharmaceuticals and other chemicals. We also discuss future opportunities for engineering and applications of the P450 systems.

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Reed, James R., J. Patrick Connick, Dongmei Cheng, George F. Cawley, and Wayne L. Backes. "Effect of homomeric P450–P450 complexes on P450 function." Biochemical Journal 446, no. 3 (August 28, 2012): 489–97. http://dx.doi.org/10.1042/bj20120636.

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Previous studies have shown that the presence of one P450 enzyme can affect the function of another. The goal of the present study was to determine if P450 enzymes are capable of forming homomeric complexes that affect P450 function. To address this problem, the catalytic activities of several P450s were examined in reconstituted systems containing NADPH–POR (cytochrome P450 reductase) and a single P450. CYP2B4 (cytochrome P450 2B4)-, CYP2E1 (cytochrome P450 2E1)- and CYP1A2 (cytochrome P450 1A2)-mediated activities were measured as a function of POR concentration using reconstituted systems containing different concentrations of P450. Although CYP2B4-dependent activities could be explained by a simple Michaelis–Menten interaction between POR and CYP2B4, both CYP2E1 and CYP1A2 activities generally produced a sigmoidal response as a function of [POR]. Interestingly, the non-Michaelis behaviour of CYP1A2 could be converted into a simple mass-action response by increasing the ionic strength of the buffer. Next, physical interactions between CYP1A2 enzymes were demonstrated in reconstituted systems by chemical cross-linking and in cellular systems by BRET (bioluminescence resonance energy transfer). Cross-linking data were consistent with the kinetic responses in that both were similarly modulated by increasing the ionic strength of the surrounding solution. Taken together, these results show that CYP1A2 forms CYP1A2–CYP1A2 complexes that exhibit altered catalytic activity.

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Omura, Tsuneo. "Structural diversity of cytochrome P450 enzyme system." Journal of Biochemistry 147, no. 3 (January 12, 2010): 297–306. http://dx.doi.org/10.1093/jb/mvq001.

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O'Donohoe, Alan, and Michael Gill. "Pharmacogenetics of the hepatic cytochrome P450 enzyme system: its relevance for prescribing in psychiatry." Irish Journal of Psychological Medicine 15, no. 3 (September 1998): 96–99. http://dx.doi.org/10.1017/s0790966700003785.

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AbstractThis article reviews the current knowledge regarding the hepatic cytochrome P450 system, with particular reference to its effect on psychotherapeutic medication. The metabolic processes – by which drugs are broken down in the liver by cytochrome P450 enzymes – are affected by genetic variation between individuals, inhibition and induction of these enzymes by other drugs, disease and age. Genetic influences and enzyme inhibition/induction are discussed in particular detail in this article.

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McLean, K. J., A. J. Dunford, M. Sabri, R. Neeli, H. M. Girvan, P. R. Balding, D. Leys, H. E. Seward, K. R. Marshall, and A. W. Munro. "CYP121, CYP51 and associated redox systems in Mycobacterium tuberculosis: towards deconvoluting enzymology of P450 systems in a human pathogen." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1178–82. http://dx.doi.org/10.1042/bst0341178.

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An extraordinary array of P450 (cytochrome P450) enzymes are encoded on the genome of the human pathogen Mycobacterium tuberculosis (Mtb) and in related mycobacteria and actinobacteria. These include the first characterized sterol 14α-demethylase P450 (CYP51), a known target for azole and triazole drugs in yeasts and fungi. To date, only two Mtb P450s have been characterized in detail: CYP51 and CYP121. The CYP121 P450 shows structural relationships with P450 enzymes involved in synthesis of polyketide antibiotics. Both P450s exhibit tight binding to a range of azole drugs (e.g. clotrimazole and fluconazole) and the same drugs also have potent effects on growth of mycobacteria (but not of e.g. Escherichia coli). Atomic structures are available for both Mtb CYP51 and CYP121, revealing modes of azole binding and intriguing mechanistic and structural aspects. This paper reviews our current knowledge of these and the other P450 systems in Mtb including recent data relating to the reversible conversion of the CYP51 enzyme between P450 (thiolate-co-ordinated) and P420 (thiol-co-ordinated) species on reduction of the haem iron in the absence of a P450 substrate. The accessory flavoprotein and iron–sulfur proteins required to drive P450 catalysis are also discussed, providing an overview of the current state of knowledge of Mtb P450 redox systems.

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Müller-Enoch, Dieter, and Hans Gruler. "Complexation of Membrane-Bound Enzyme Systems." Zeitschrift für Naturforschung C 55, no. 9-10 (October 1, 2000): 747–52. http://dx.doi.org/10.1515/znc-2000-9-1012.

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Abstract The effect of changes in the N-terminal membrane-binding domain of cytochrome P450 forms and NADPH-cytochrome P450 reductase types on the cytochrome P450-dependent monooxygenase activities, has been examined. The nifedipine oxidase activity of two human P450 forms (CYP3A4, CYP3A4NF14) which differ only in their primary structure by ten amino acid residues in the N-terminal membrane-binding domain, yields nearly the same catalytic cycle time τ =2.65 ± 0.15 s, due to their identical cytosolic catalytic protein structure. In contrast, the complex formation process ([P450]+[reductase]↔[complex]) described by the dissociation constant KD at high substrate concentration ([S]>>KS) and low product concentration ( [ P ]<<Kp ) is determined to be KD/[P450]ᴏ = 0.3 and 2.0, respectively. These values reflect large differences in the affinity of both P450 forms for the same type of reductase which is only due to their modified membrane-binding domains. In the present work, it has been shown for the first time, that the membrane-binding domain of cytochrome P450 enzymes determines the complexation process of the binary P450:reductase system. Furthermore, the nifedipine oxidase activity of the human CYP3A4 form reconstituted with two different types of reductase from human and rabbit also has the same catalytic cycle time τ = 2.65 ± 0.15 s. This result is based on the similarity of the primary structure of the cytosolic catalytic domain of both reductase types. However, the complex was formed with different dissociation constants of KD/[P450]ᴏ = 0.3 and 4.7, respectively. This different affinity of both reductase types to the same P450 form is interpreted as a consequence of the substantial alteration of the amino acids in the N-terminal primary structure of their membrane-binding domains. 7-Ethoxycoumarin O-deethylase activity of two rat P450 forms (CYP2B1 and CYP1A1) were reconstituted with the same rat reductase. The catalytic cycle time for each P450 form is τ = 1.8 and 0.6 s, respectively. Correspondingly, the complex formation process controlled by the dissociation constant KD has changed from KD/[P450]ᴏ = 2.3 to 1.7, respectively. This is because both forms differ in their cytosolic as well as in their membranebinding domains.

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van den Brink, Hans (J ). M., Robert F. M. van Gorcom, Cees A. M. J. J. van den Hondel, and Peter J. Punt. "Cytochrome P450 Enzyme Systems in Fungi." Fungal Genetics and Biology 23, no. 1 (February 1998): 1–17. http://dx.doi.org/10.1006/fgbi.1997.1021.

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Chun, Y. J., T. Shimada, M. R. Waterman, and F. P. Guengerich. "Understanding electron transport systems of Streptomyces cytochrome P450." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1183–85. http://dx.doi.org/10.1042/bst0341183.

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Streptomyces spp. are known to produce various types of biologically active compounds including antibiotics, antiparasitic agents, herbicides and immunosuppressants. P450 (cytochrome P450) enzymes may have key roles in these biosynthetic and biotransformation reactions. Recent genomic analysis of Streptomyces coelicolor A3(2) indicates that S. coelicolor may have six ferredoxins (Fdxs), four putative Fdx reductases (FdRs) and 18 P450 genes. However, there are few clues to explain the mechanisms and functions of Streptomyces P450 systems. To solve these questions, we have expressed and purified five S. coelicolor P450s, four FdRs and six Fdxs in Escherichia coli. Of the purified P450s, CYP105D5 has fatty acid hydroxylation activity in a system reconstituted with putidaredoxin reductase and Fdx4 or with spinach FdR and spinach Fdx, although the reconstitutions with FdR2 or FdR3 and any of the Fdxs did not support CYP105D5-catalysed oleic acid hydroxylation. Elucidation of the detailed mechanisms of electron transport system for Streptomyces P450 may provide the perspective for usefulness of P450s as a biocatalyst.

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Watkins, Vish S., Ron E. Polk, and Jennifer L. Stotka. "Drug Interactions of Macrolides: Emphasis on Dirithromycin." Annals of Pharmacotherapy 31, no. 3 (March 1997): 349–56. http://dx.doi.org/10.1177/106002809703100314.

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Objective To describe the drug interactions of dirithromycin, a new macrolide, and to compare them with those of other macrolides. Data Sources A literature search was performed using MEDLINE to identify articles published between January 1980 and July 1995 concerning the drug interactions of macrolides. Published abstracts were also examined. All studies using dirithromycin were performed under the sponsorship of Eli Lilly and Company. Data Synthesis Erythromycin, the first macrolide discovered, is metabolized by the cytochrome P450 enzyme system. By decreasing their metabolism, erythromycin can interact with other drugs metabolized by the cytochrome P450 enzymes. The lack of such interactions would be a desirable feature in a newer macrolide. We describe studies performed to detect any interactions of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, and ethinyl estradiol. The studies showed that dirithromycin, like azithromycin, is much less likely to cause the interactions detected with clarithromycin and erythromycin. A review of the literature showed differences among macrolides in their abilities to inhibit cytochrome P450 enzymes and, thus, to cause drug–drug interactions. Erythromycin and clarithromycin inhibit cytochrome P450 enzymes, and have been implicated in clinically significant interactions. Azithromycin and dirithromycin neither inhibit cytochrome P450 enzymes nor are implicated in clinically significant drug–drug interactions. Conclusions Dirithromycin, a new macrolide, does not inhibit the cytochrome P450 enzyme system. The concomitant use of dirithromycin with cyclosporine, theophylline, terfenadine, warfarin, or ethinyl estradiol was studied in pharmacokinetic and pharmacodynamic studies. In vitro, dirithromycin did not bind cytochrome P450. In healthy subjects, erythromycin increases the clearance of cyclosporine by 51%, whereas dirithromycin causes no significant changes in the pharmacokinetics of cyclosporine. In kidney transplant recipients, administration of dirithromycin was associated with a significant (p < 0.003) decrease of 17.4% in the clearance of cyclosporine. In patients taking low-dose estradiol, the administration of dirithromycin caused a significant (p < 0.03) increase of 9.9% in the clearance of ethinyl estradiol; escape ovulation did not occur. Unlike erythromycin and clarithromycin, dirithromycin had no significant effects on the pharmacokinetics of theophylline, terfenadine, or warfarin. The alterations typical of drug interactions that are based on inhibition of the cytochrome P450 system occurring with erythromycin and clarithromycin were not observed with dirithromycin.

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Kool, Jeroen, Sebastiaan M. van Liempd, Rawi Ramautar, Tim Schenk, John H. N. Meerman, Hubertus Irth, Jan N. M. Commandeur, and Nico P. E. Vermeulen. "Development of a Novel Cytochrome P450 Bioaffinity Detection System Coupled Online to Gradient Reversed-Phase High-Performance Liquid Chromatography." Journal of Biomolecular Screening 10, no. 5 (August 2005): 427–36. http://dx.doi.org/10.1177/1087057105274904.

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A high-resolution screening platform, coupling online affinity detection for mammalian cytochrome P450s (Cyt P450s) to gradient reversed-phase high-performance liquid chromatography (HPLC), is described. To this end, the onlineCyt P450 enzyme affinity detection (EAD) system was optimized for enzyme (β-NF-induced rat liver microsomes), probe substrate (ethoxyresorufine), and organic modifier (methanol or acetonitrile). The optimized Cyt P450 EAD system has first been evaluated in a flow injection analysis (FIA) mode with 7 known ligands of Cyt P450 1A1/1A2 (β-naphthoflavone, ßnaphthoflavone, ellipticine, 9-hydroxy-ellipticine, fluvoxamine, caffein, and phenacetin). Subsequently, IC 50 valueswere online in FIA-mode determined and compared with those obtained with standardmicrosomal assay conditions. The IC 50 values obtained with the online Cyt P450 EAD system agreed well with the IC 50 values obtained in the standard assays. For highaffinity ligands ofCyt P450 1A1/1A2, detection limits of 1 to 3 pmol injected ( n= 3; signal to noise [S/N] = 3) were obtained. The individual inhibitory properties of ligands in mixtures of the ligands were subsequently investigated using an optimized Cyt P450 EAD system online coupled to gradient HPLC. Using the integrated online gradient HPLC Cyt P450 EAD platform, detection limits of 10 to 25 pmol injected ( n= 1; S/N= 3) were obtained for high-affinity ligands. It is concluded that this novel screening technology offers new perspectives for rapid and sensitive screening of individual compounds in mixtures exhibiting affinity for liver microsomal Cyt P450s.

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Ito, Michihiro, Ikuo Sato, Masumi Ishizaka, Shin-ichiro Yoshida, Motoo Koitabashi, Shigenobu Yoshida, and Seiya Tsushima. "Bacterial Cytochrome P450 System Catabolizing the Fusarium Toxin Deoxynivalenol." Applied and Environmental Microbiology 79, no. 5 (December 28, 2012): 1619–28. http://dx.doi.org/10.1128/aem.03227-12.

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ABSTRACTDeoxynivalenol (DON) is a natural toxin of fungi that causeFusariumhead blight disease of wheat and other small-grain cereals. DON accumulates in infected grains and promotes the spread of the infection on wheat, posing serious problems to grain production. The elucidation of DON-catabolic genes and enzymes in DON-degrading microbes will provide new approaches to decrease DON contamination. Here, we report a cytochrome P450 system capable of catabolizing DON inSphingomonassp. strain KSM1, a DON-utilizing bacterium newly isolated from lake water. The P450 geneddnAwas cloned through an activity-based screening of a KSM1 genomic library. The genes of its redox partner candidates (flavin adenine dinucleotide [FAD]-dependent ferredoxin reductase and mitochondrial-type [2Fe-2S] ferredoxin) were not found adjacent toddnA; the redox partner candidates were further cloned separately based on conserved motifs. The DON-catabolic activity was reconstitutedin vitroin an electron transfer chain comprising the three enzymes and NADH, with a catalytic efficiency (kcat/Km) of 6.4 mM−1s−1. The reaction product was identified as 16-hydroxy-deoxynivalenol. A bioassay using wheat seedlings revealed that the hydroxylation dramatically reduced the toxicity of DON to wheat. The enzyme system showed similar catalytic efficiencies toward nivalenol and 3-acetyl deoxynivalenol, toxins that frequently cooccur with DON. These findings identify an enzyme system that catabolizes DON, leading to reduced phytotoxicity to wheat.

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Coon, Minor J. "CYTOCHROME P450: Nature's Most Versatile Biological Catalyst." Annual Review of Pharmacology and Toxicology 45, no. 1 (September 22, 2005): 1–25. http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100030.

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The author describes studies that led to the resolution and reconstitution of the cytochrome P450 enzyme system in microsomal membranes. The review indicates how purification and characterization of the cytochromes led to rigorous evidence for multiple isoforms of the oxygenases with distinct chemical and physical properties and different but somewhat overlapping substrate specificities. Present knowledge of the individual steps in the P450 and reductase reaction cycles is summarized, including evidence for the generation of multiple functional oxidants that may contribute to the exceptional diversity of the reactions catalyzed.

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Kitteringham, Neil R., Munir Pirmohamed, and B. Kevin Park. "3 The pharmacology of the cytochrome P450 enzyme system." Baillière's Clinical Anaesthesiology 12, no. 2 (June 1998): 191–211. http://dx.doi.org/10.1016/s0950-3501(98)80028-7.

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Andersson, Tommy, and Lars Förlin. "Regulation of the cytochrome P450 enzyme system in fish." Aquatic Toxicology 24, no. 1-2 (November 1992): 1–19. http://dx.doi.org/10.1016/0166-445x(92)90014-e.

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Rendic, Slobodan, and Frederick Peter Guengerich. "Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters." Current Drug Metabolism 21, no. 14 (December 30, 2020): 1127–35. http://dx.doi.org/10.2174/1389200221999201208211537.

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Background:: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. Methods:: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). Results:: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. Conclusions:: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.

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Nguyen, Kim-Thoa, Ngọc-Lan Nguyen, Nguyen Van Tung, Huy Hoang Nguyen, Mohammed Milhim, Thi-Thanh-Xuan Le, Thi-Hong-Nhung Lai, Thi-Tuyet-Minh Phan, and Rita Bernhardt. "A Novel Thermostable Cytochrome P450 from Sequence-Based Metagenomics of Binh Chau Hot Spring as a Promising Catalyst for Testosterone Conversion." Catalysts 10, no. 9 (September 18, 2020): 1083. http://dx.doi.org/10.3390/catal10091083.

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Biotechnological applications of cytochromes P450 show difficulties, such as low activity, thermal and/or solvent instability, narrow substrate specificity and redox partner dependence. In an attempt to overcome these limitations, an exploitation of novel thermophilic P450 enzymes from nature via uncultured approaches is desirable due to their great advantages that can resolve nearly all mentioned impediments. From the metagenomics library of the Binh Chau hot spring, an open reading frame (ORF) encoding a thermostable cytochrome P450—designated as P450-T3—which shared 66.6% amino acid sequence identity with CYP109C2 of Sorangium cellulosum So ce56 was selected for further identification and characterization. The ORF was synthesized artificially and heterologously expressed in Escherichia coli C43(DE3) using the pET17b system. The purified enzyme had a molecular weight of approximately 43 kDa. The melting temperature of the purified enzyme was 76.2 °C and its apparent half-life at 60 °C was 38.7 min. Redox partner screening revealed that P450-T3 was reduced well by the mammalian AdR-Adx4-108 and the yeast Arh1-Etp1 redox partners. Lauric acid, palmitic acid, embelin, retinoic acid (all-trans) and retinoic acid (13-cis) demonstrated binding to P450-T3. Interestingly, P450-T3 also bound and converted testosterone. Overall, P450-T3 might become a good candidate for biocatalytic applications on a larger scale.

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Touw, D. J., W. M. A. Verhoeven, and J. B. G. M. Noten. "Het cytochroom P450 enzymsysteem: wat is de relevantie voor de praktijk? Deel II, interacties." Acta Neuropsychiatrica 10, no. 3 (September 1998): 58–62. http://dx.doi.org/10.1017/s0924270800036589.

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SummaryIn man a great interindividual variability exists in the oxidative capacity to metabolize drugs. A major factor contributing to this phenomenon is the genetically determined hydroxyla-tion-capacity of the cytochrome P450 enzyme system. The cytochrome P450 system comprises of several isozymes. For several isozymes (CYP2D6, CYP2C) a genetically based hydroxylation capacity has been demonstrated. A frequency distribution of the clearance shows a bimodal distribution with poor and extensive metabolizers. Applying standard dosing schemes of the drugs that are predominantly metabolised by these isozymes, a considerable number of patients will be intoxicated because of poor metabolism. In general, cytochrome P450 capacity is limited and substrate-affinity is high. Henceforth cytochrome P450 isozymes are likely targets for pharmacokinetic interactions.

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Girvan, H. M., T. N. Waltham, R. Neeli, H. F. Collins, K. J. McLean, N. S. Scrutton, D. Leys, and A. W. Munro. "Flavocytochrome P450 BM3 and the origin of CYP102 fusion species." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1173–77. http://dx.doi.org/10.1042/bst0341173.

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Flavocytochrome P450 (cytochrome P450) BM3 is an intensively studied model system within the P450 enzyme superfamily, and is a natural fusion of a P450 to its P450 reductase redox partner. The fusion arrangement enables efficient electron transfer within the enzyme and a catalytic efficiency that cannot be matched in P450 systems from higher organisms. P450 BM3's potential for industrially relevant chemical transformations is now recognized, and variants with biotechnological applications have been constructed. Simultaneously, structural and mechanistic studies continue to reveal the intricate mechanistic details of this enzyme, including its dimeric organization and the relevance of this quaternary structure to catalysis. Homologues of BM3 have been found in several bacteria and fungi, indicating important physiological functions in these microbes and enabling first insights into evolution of the enzyme family. This short paper deals with recent developments in our understanding of structure, function, evolution and biotechnological applications of this important P450 system.

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Munro, Andrew W., Kirsty J. McLean, Job L. Grant, and Thomas M. Makris. "Structure and function of the cytochrome P450 peroxygenase enzymes." Biochemical Society Transactions 46, no. 1 (February 6, 2018): 183–96. http://dx.doi.org/10.1042/bst20170218.

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The cytochromes P450 (P450s or CYPs) constitute a large heme enzyme superfamily, members of which catalyze the oxidative transformation of a wide range of organic substrates, and whose functions are crucial to xenobiotic metabolism and steroid transformation in humans and other organisms. The P450 peroxygenases are a subgroup of the P450s that have evolved in microbes to catalyze the oxidative metabolism of fatty acids, using hydrogen peroxide as an oxidant rather than NAD(P)H-driven redox partner systems typical of the vast majority of other characterized P450 enzymes. Early members of the peroxygenase (CYP152) family were shown to catalyze hydroxylation at the α and β carbons of medium-to-long-chain fatty acids. However, more recent studies on other CYP152 family P450s revealed the ability to oxidatively decarboxylate fatty acids, generating terminal alkenes with potential applications as drop-in biofuels. Other research has revealed their capacity to decarboxylate and to desaturate hydroxylated fatty acids to form novel products. Structural data have revealed a common active site motif for the binding of the substrate carboxylate group in the peroxygenases, and mechanistic and transient kinetic analyses have demonstrated the formation of reactive iron-oxo species (compounds I and II) that are ultimately responsible for hydroxylation and decarboxylation of fatty acids, respectively. This short review will focus on the biochemical properties of the P450 peroxygenases and on their biotechnological applications with respect to production of volatile alkenes as biofuels, as well as other fine chemicals.

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Preskorn, Sheldon H., Alice I. Nichols, Jeffrey Paul, Albena L. Patroneva, Eileen C. Helzner, and Christine J. Guico-Pabia. "Effect of Desvenlafaxine on the Cytochrome P450 2D6 Enzyme System." Journal of Psychiatric Practice 14, no. 6 (November 2008): 368–78. http://dx.doi.org/10.1097/01.pra.0000341891.43501.6b.

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Zamir, Lolita Ora, and Carole Abi Farah. "Is Fusarium culmorum isotrichodermin-15-hydroxylase different from other fungal species?" Canadian Journal of Microbiology 46, no. 2 (February 1, 2000): 143–49. http://dx.doi.org/10.1139/w99-116.

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Fusarium spp. are ubiquitous fungi infecting cereals and grains, and therefore constitute a major problem for agriculture. Their trichothecene metabolites, and in particular deoxynivalenol and its 3-acetylated derivative, are the mycotoxins involved. The major metabolite produced by Fusarium culmorum is 3-acetyldeoxynivalenol. Studies in vivo with Fusarium culmorum have established that its tricyclic intermediate, isotrichodermin, is a major biosynthetic precursor, which is hydroxylated at position 15 to give 15-deacetylcalonectrin, prior to being converted to the product. In a preliminary in vitro investigation of the cell-free system involved in this transformation, we suggested that cytochrome P450 enzymes are not involved. In this paper, the isotrichodermin-15-hydroxylase from the microsomal fraction of Fusarium culmorum was solubilized and partially purified (60 fold). Our studies with cofactors indicate that this enzyme is a flavoprotein, and the inducers tested highly indicate that indeed the hydroxylase is not attached to cytochrome P450. This is particularly interesting, since the only other enzyme catalyzing the same reaction isolated from Fusarium sporotrichiodes is attached to cytochrome P450. Key words: trichothecene, Fusarium culmorum, cell-free system, isotrichodermin, 15-deacetylcalonectrin, flavoprotein.

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Xu, Xuan, Jing Qian, Jiachao Yu, Yuanjian Zhang, and Songqin Liu. "Cytochrome P450 enzyme functionalized-quantum dots as photocatalysts for drug metabolism." Chem. Commun. 50, no. 57 (2014): 7607–10. http://dx.doi.org/10.1039/c4cc01717j.

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Belsare, Ketaki D., Anna Joëlle Ruff, Ronny Martinez, and Ulrich Schwaneberg. "Insights on intermolecular FMN-heme domain interaction and the role of linker length in cytochrome P450cin fusion proteins." Biological Chemistry 401, no. 11 (October 25, 2020): 1249–55. http://dx.doi.org/10.1515/hsz-2020-0134.

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AbstractCytochrome P450s are an important group of enzymes catalyzing hydroxylation, and epoxidations reactions. In this work we describe the characterization of the CinA–CinC fusion enzyme system of a previously reported P450 using genetically fused heme (CinA) and FMN (CinC) enzyme domains from Citrobacter braaki. We observed that mixing individually inactivated heme (-) with FMN (-) domain in the CinA-10aa linker - CinC fusion constructs results in recovered activity and the formation of (2S)-2β-hydroxy,1,8-cineole (174 µM), a similar amount when compared to the fully functional fusion protein (176 µM). We also studied the effect of the fusion linker length in the activity complementation assay. Our results suggests an intermolecular interaction between heme and FMN parts from different CinA–CinC fusion protein similar to proposed mechanisms for P450 BM3 on the other hand, linker length plays a crucial influence on the activity of the fusion constructs. However, complementation assays show that inactive constructs with shorter linker lengths have functional subunits, and that the lack of activity might be due to incorrect interaction between fused enzymes.

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Guengerich, F. Peter, Clayton J. Wilkey, and Thanh T. N. Phan. "Human cytochrome P450 enzymes bind drugs and other substrates mainly through conformational-selection modes." Journal of Biological Chemistry 294, no. 28 (May 30, 2019): 10928–41. http://dx.doi.org/10.1074/jbc.ra119.009305.

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Cytochrome P450 (P450) enzymes are major catalysts involved in the oxidations of most drugs, steroids, carcinogens, fat-soluble vitamins, and natural products. The binding of substrates to some of the 57 human P450s and other mammalian P450s is more complex than a two-state system and has been proposed to involve mechanisms such as multiple ligand occupancy, induced-fit, and conformational-selection. Here, we used kinetic analysis of binding with multiple concentrations of substrates and computational modeling of these data to discern possible binding modes of several human P450s. We observed that P450 2D6 binds its ligand rolapitant in a mechanism involving conformational-selection. P450 4A11 bound the substrate lauric acid via conformational-selection, as did P450 2C8 with palmitic acid. Binding of the steroid progesterone to P450 21A2 was also best described by a conformational-selection model. Hexyl isonicotinate binding to P450 2E1 could be described by either a conformational-selection or an induced-fit model. Simulation of the binding of the ligands midazolam, bromocriptine, testosterone, and ketoconazole to P450 3A4 was consistent with an induced-fit or a conformational-selection model, but the concentration dependence of binding rates for varying both P450 3A4 and midazolam concentrations revealed discordance in the parameters, indicative of conformational-selection. Binding of the P450s 2C8, 2D6, 3A4, 4A11, and 21A2 was best described by conformational-selection, and P450 2E1 appeared to fit either mode. These findings highlight the complexity of human P450-substrate interactions and that conformational-selection is a dominant feature of many of these interactions.

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Benković, Goran, Hrvoje Rimac, Željan Maleš, Siniša Tomić, Zoran Lončar, and Mirza Bojić. "Characterization of O-demethylations and Aromatic Hydroxylations Mediated by Cytochromes P450 in the Metabolism of Flavonoid Aglycons." Croatica chemica acta 92, no. 1 (2019): 115–23. http://dx.doi.org/10.5562/cca3528.

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One of the most important groups of metabolic enzymes is cytochrome P450 superfamily. These enzymes are important in terms of the catalytic diversity and the large number of xenobiotics that are detoxified or activated by converting to reactive metabolites. Flavonoids are xenobiotics to which humans are exposed through diet. Data on their oxidative metabolism mediated by cytochromes P450 are limited. The aim of this study was to determine the enzymatic kinetics of O-demethylation and aromatic hydroxylation of flavonoid aglycons on recombinant cytochrome P450 enzymes and human liver microsomes systems. The study was performed on ten flavonoids, namely 3,7-dihydroxyflavone, 7-hydroxyflavone, acacetin, apigenin, flavone, galangin, kaempferol, naringenin, sakuranetin, and tangeretin using liquid chromatography coupled with mass spectrometry and UV detector. Most relevant enzyme involved in metabolism of flavonoid aglycons is CYP1A2, and its catalytic effectiveness ranges from 0.5 to 2.9 × 106 M–1 min–1. Having in mind high expression and involvement of CYP1A2 in metabolism of xenobiotics including drugs, and its intraindividual differences in expression and activity, potential of drug-flavonoid competitive interactions/inhibitions should be considered when consuming dietary supplement and foods rich in flavonoids.

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Shiba, Dai, and Norio Shimamoto. "Involvement of cytochrome P450 enzyme system in quinone-induced hepatocyte injury." Japanese Journal of Pharmacology 82 (2000): 101. http://dx.doi.org/10.1016/s0021-5198(19)47871-2.

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van der Weide, J., and L. S. W. Steijns. "Cytochrome P450 Enzyme System: Genetic Polymorphisms and Impact on Clinical Pharmacology." Annals of Clinical Biochemistry: An international journal of biochemistry and laboratory medicine 36, no. 6 (November 1, 1999): 722–29. http://dx.doi.org/10.1177/000456329903600604.

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Haehner, Thomas, Ulrich Massing, Torsten Diesinger, and Dieter Müller-Enoch. "Inhibition of Cytochrome P450 Mediated Enzyme Activity by Alkylphosphocholines." Zeitschrift für Naturforschung C 59, no. 7-8 (August 1, 2004): 599–605. http://dx.doi.org/10.1515/znc-2004-7-826.

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AbstractThe inhibitory potency of four alkylphospholipids: rac-1-O-phosphocholine-2-hydroxy-octadecane (rac-2-OH), rac-1-O-phosphocholine-2-O-acetyl-octadecane (rac-2-O-acetyl), rac-1- O-phosphocholine-2-amino-octadecane (rac-2-NH2) and rac-1-O-phosphocholine-2-N-acetyloctadecane (rac-2-N-acetyl), on the cytochrome P450-dependent monooxygenase activity has been evaluated. The IC50 values of the alkylphosphocholines with 7-ethoxycoumarin as substrate in liver microsomal fractions of PB-treated rats and with a reconstituted CYP2B1: NADPH-P450-reductase system are in the range of 3.2D5.0 μм and 2.8D3.5 μм, respectively. Lineweaver-Burk plots with the inhibitors in concentrations that were found to cause roughly a 50% inhibition and with 7-ethoxycoumarin as substrate revealed for all four alkylphospholipids a competitive inhibition type. The degree of the competitive inhibition is quantified by the Ki values. With liver microsomal fractions of PB-treated rats, the Ki values of rac-2-OH (Ki = 1.36 μм) and rac-2-O-acetyl (Ki = 1.33 μm) differs slightly from those of rac-2-NH2 (Ki = 2.2 μм) and rac-2-N-acetyl (Ki = 2.2 μм), but with the reconstituted CYP2B1: NADPHP450- reductase system all Ki values are in the small range of 1.8 D 2.6 μм, indicating that the short substituted group at the 2-position (OH; O-acetyl; NH2; N-acetyl) of the long chain octadecanol part of the phosphodiesters exhibit no essential role on the strong inhibitory potency of these alkylphosphocholines on the 7-ethoxycoumarin-O-deethylase activity.

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Reed, Lindsay, Volker M. Arlt, and David H. Phillips. "The role of cytochrome P450 enzymes in carcinogen activation and detoxication: an in vivo–in vitro paradox." Carcinogenesis 39, no. 7 (May 3, 2018): 851–59. http://dx.doi.org/10.1093/carcin/bgy058.

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Cytochrome P450 enzyme systems have been widely used in vitro to determine the pathways of activation of procarcinogens, but paradoxically, these same enzymes can play a more predominant role in carcinogen detoxification in vivo.

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Noten, J. B. G. M., W. M. A. Verhoeven, S. Tuinier, and D. Touw. "Therapeutic drug monitoring." Acta Neuropsychiatrica 11, no. 1 (March 1999): 15–16. http://dx.doi.org/10.1017/s0924270800036309.

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SUMMARYThe cytochrome P450 iso-enzyme system plays a key role in the biotransformation of many drugs, including psychotropics. Its activity is determined by both genetic and environmental factors. The most important iso-enzymes for psychiatry in general are P450 IID6, 3A4 and 1A2. Knowledge about the involvement of these enzymes and biotransformation processes is mandatory because of the individual variability in their metabolic capacity. Regular measurement of plasmaconcentrations of (psycho)pharmacological compounds is therefore essential. In addition, the potential value of pheno- and/or genotyping has to be investigated.

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Henderson, C. J., A. Sahraouei, and C. R. Wolf. "Cytochrome P450s and chemoprevention." Biochemical Society Transactions 28, no. 2 (February 1, 2000): 42–46. http://dx.doi.org/10.1042/bst0280042.

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The cytochrome P450 mono-oxygenase system represents a major defence against chemical challenge from the environment, constituting part of an adaptive response mounted by an organism following exposure to harmful agents. Cytochrome P450s are also able to catalyse the activation of compounds to toxic products, and participate in a variety of essential ‘housekeeping’ functions, such as biosynthesis of steroid hormones and fatty acid oxidation. It is clear that the modulation of expression of these enzymes can have a significant effect on chemical toxicity, carcinogenicity and mutagenicity. The concept of cancer chemoprevention, i.e. the administration of a (non-toxic) chemical or dietary component in order to prevent neoplastic disease or to inhibit its progression, is an attractive one. Despite this, relatively little work has been done to characterize the ability of putative chemopreventive agents to modulate P450 expression, or to understand the interaction between P450s and chemopreventive agents. Before chemopreventive treatment can become a reality, it is essential that this complex issue is addressed; for instance, it is likely that any single chemopreventive agent will induce more than one P450 isoenzyme, and while altered expression of a particular P450 may attenuate the effects of one toxic agent, the effects of others might well be potentiated. Our laboratory has created a transgenic mouse line in which the rat CYP1A1 promoter drives expression of the β-galactosidase gene. These mice can be used to define which compounds act via the Ah receptor, in which tissues, and at which stage of development. We are currently developing another mouse line in which β-galactosidase expression is controlled by the mouse GstA1 promoter, allowing us to define the role of the antioxidant responsive element in the action of chemopreventive agents. Finally, using cre-1oxP transgenic technology, we have generated a mouse line in which P450 reductase can be deleted in a conditional, i.e. tissue-specific, manner, permitting us to investigate the role of P450s in chemoprevention in a more defined manner.

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Wu, Zhexue, Doohyun Lee, Jeongmin Joo, Jung-Hoon Shin, Wonku Kang, Sangtaek Oh, Do Yup Lee, et al. "CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems." Antimicrobial Agents and Chemotherapy 57, no. 11 (August 19, 2013): 5448–56. http://dx.doi.org/10.1128/aac.00843-13.

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ABSTRACTAlbendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazolein vivo.

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Amal Al Omari and Daryl J. Murry. "Pharmacogenetics of the Cytochrome P450 Enzyme System: Review of Current Knowledge and Clinical Significance." Journal of Pharmacy Practice 20, no. 3 (June 2007): 206–18. http://dx.doi.org/10.1177/0897190007304821.

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Genetic variation in drug metabolizing enzymes is an important contributor to interindividual variation in drug disposition and response and is associated with significant clinical consequences. Many commonly used drugs are dependent on the cytochrome P450 monooxygenase enzymes (CYP450) for their metabolism and elimination. At present, more than 57 active human CYP450 genes are known, and the majority of these genes are polymorphic. Despite the large number of CYP450 genes, only the CYP1, CYP2, and CYP3 families of enzymes have a major role in drug metabolism. Approximately 10 CYP450s are responsible for the metabolism of a large number of pharmacologic agents in human beings. The polymorphic forms of the CYP450s are responsible for the development of a significant number of adverse drug reactions and may also contribute to drug response. Genetic polymorphisms have now been identified in the genes encoding all the main CYP450s that contribute to drug and other xenobiotic metabolism, and there are marked interethnic differences in the distribution and frequency of variant alleles. A review of the progress in the pharmacogenetics of P450s that are important for drug metabolism is presented with particular emphasis on the clinical relevance of this research.

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WANG, Xiu Jun, Mark CHAMBERLAIN, Olga VASSIEVA, Colin J. HENDERSON, and C. Roland WOLF. "Relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (POR) null mice." Biochemical Journal 388, no. 3 (June 7, 2005): 857–67. http://dx.doi.org/10.1042/bj20042087.

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Cytochrome P450 reductase is the unique electron donor for microsomal cytochrome P450s; these enzymes play a major role in the metabolism of endogenous and xenobiotic compounds. In mice with a liver-specific deletion of cytochrome P450 reductase, hepatic cytochrome P450 activity is ablated, with consequent changes in bile acid and lipid homoeostasis. In order to gain insights into the metabolic changes resulting from this phenotype, we have analysed changes in hepatic mRNA expression using microarray analysis and real-time PCR. In parallel with the perturbations in bile acid levels, changes in the expression of key enzymes involved in cholesterol and lipid homoeostasis were observed in hepatic cytochrome P450 reductase null mice. This was characterized by a reduced expression of Cyp7b1, and elevation of Cyp7a1 and Cyp8b1 expression. The levels of mRNAs for other cytochrome P450 genes, including Cyp2b10, Cyp2c29, Cyp3a11 and Cyp3a16, were increased, demonstrating that endogenous factors play a role in regulating the expression of these proteins and that the increases are due, at least in part, to altered levels of transcripts. In addition, levels of mRNAs encoding genes involved in glycolysis and lipid transport were also increased; the latter may provide an explanation for the increased hepatic lipid content observed in the hepatic null mice. Serum testosterone and oestradiol levels were lowered, accompanied by significantly decreased expression of Hsd3b2 (3β-hydroxy-Δ5-steroid dehydrogenase-2), Hsd3b5 (3β-hydroxy-Δ5-steroid dehydrogenase-5) and Hsd11b1 (11β-hydroxysteroid dehydrogenase type 1), key enzymes in steroid hormone metabolism. These microarray data provide important insights into the control of metabolic pathways by the cytochrome system.

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Armstrong, Steven, and Kenneth W. Renton. "Hepatic cytochrome P450 and related drug biotransformation during an outbreak of mouse hepatitis virus in a colony of Swiss BALB/c mice." Canadian Journal of Physiology and Pharmacology 71, no. 2 (February 1, 1993): 188–90. http://dx.doi.org/10.1139/y93-027.

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Mouse hepatitis is a common highly infectious virus of the Coronaviridae family that commonly infects laboratory colonies of BALB/c mice. In a natural outbreak of this disease in our institution we demonstrated that mouse hepatitis virus appears to have little or no effect on the levels of cytochrome P450 or on the activities of ethoxyresorufin O-dealkylase and benzyloxy resorufin O-dealkylase in hepatic microsomes. Antibody titers for the virus were elevated in ail mice tested and were negative in a control uninfected group. In a number of studies carried out over a period of months during the active outbreak we did not observe lower levels of cytochrome P450 in comparison with infectious free periods. Although the activation of host defence mechanisms and infections are well known to diminish the cytochrome P450 enzyme system in the liver, these results indicate that during a period of confirmed active infection with mouse hepatitis virus there was no evidence of an impairment in drug biotransformation enzymes.Key words: cytochrome P450, mouse hepatitis, infection, drug metabolism.

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Standop, Jens, Matthias Schneider, Alexis Ulrich, Markus W. Büchler, and Parviz M. Pour. "Differences in Immunohistochemical Expression of Xenobiotic-Metabolizing Enzymes Between Normal Pancreas, Chronic Pancreatitis and Pancreatic Cancer." Toxicologic Pathology 31, no. 5 (August 2003): 506–13. http://dx.doi.org/10.1080/01926230390226041.

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Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer. On the other hand, CYP 1A1 and 2E1 antibody staining was less frequently observed in chronic pancreatitis. In all specimens with pancreatic polypeptide (PP)-rich regions (pancreas head), more islet cells than ductal and acinar cells were immunopositive. Moreover, the immunoreactivity of islet cells from PP-rich specimens with anti-CYP antibodies was consistently more frequent and intense than in islet cells from PP-poor areas (body and tail). Immunoreactivity for xenobiotic-metabolizing enzymes was frequently observed in the normal pancreas, chronic pancreatitis, and pancreatic cancer, and displayed differences of its frequency and intensity between the 3 groups. Considering immunohistochemical evidence of enzyme expression and pancreatic blood supply together, islet cells appear to be an important and possible early site of CYP-enzyme induction in pancreatic diseases.

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Li, Z., S. Okano, K. Yoshinari, T. Miyamoto, Y. Yamazoe, K. Shinya, K. Ioku, and N. Kasai. "Soft-hydrothermal processing of red cedar bedding reduces its induction of cytochrome P450 in mouse liver." Laboratory Animals 43, no. 2 (April 2009): 205–11. http://dx.doi.org/10.1258/la.2008.007146.

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Red cedar-derived bedding materials cause changes in cytochrome P450-dependent microsomal enzyme systems in laboratory animals. We examined the effect of essential oil of red cedar (EORC), as well as the effect of bedding from which it had been removed, on the hepatic expression cytochrome P450s in mice. EORC was obtained from liquid extracts of red cedar bedding by a soft-hydrothermal process and was administered orally to mice. Between days 1 and 2 after administration, hepatic P450s were significantly induced as follows: CYP3As, 7.1×; CYP1As, 1.6×; CYP2E1, 1.5×; CYP2Cs, 1.6×. A housing study of mice indicated that red cedar bedding increased the levels of these P450s in mouse liver, whereas mice housed in cedar bedding from which EORC had been removed (ST-cedar bedding) showed significantly lower levels of P450s, especially CYP3As, CYP1As and CYP2E1. Soft-hydrothermal processing partially removed many components of EORC. In particular, several volatile sesquiterpenes, naphthalene-derived aromatics and 4,4-dimethyl-13α-androst-5-ene were decreased in the ST-cedar bedding, suggesting that these may be responsible for P450 induction. This study demonstrated that the removal of these volatile compounds by soft-hydrothermal processing can decrease the hepatic P450-inducing effect of red cedar bedding.

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Davydov, Dmitri R., Nadezhda Y. Davydova, Elena V. Sineva, Irina Kufareva, and James R. Halpert. "Pivotal role of P450–P450 interactions in CYP3A4 allostery: the case of α-naphthoflavone." Biochemical Journal 453, no. 2 (June 28, 2013): 219–30. http://dx.doi.org/10.1042/bj20130398.

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We investigated the relationship between oligomerization of CYP3A4 (cytochrome P450 3A4) and its response to ANF (α-naphthoflavone), a prototypical heterotropic activator. The addition of ANF resulted in over a 2-fold increase in the rate of CYP3A4-dependent debenzylation of 7-BFC [7-benzyloxy-4-(trifluoromethyl)coumarin] in HLM (human liver microsomes), but failed to produce activation in BD Supersomes™ or Baculosomes® containing recombinant CYP3A4 and NADPH-CPR (cytochrome P450 reductase). However, incorporation of purified CYP3A4 into Supersomes™ containing only recombinant CPR reproduced the behaviour observed with HLM. The activation in this system was dependent on the surface density of the enzyme. Although no activation was detectable at an L/P (lipid/P450) ratio ≥750, it reached 225% at an L/P ratio of 140. To explore the relationship between this effect and CYP3A4 oligomerization, we probed P450–P450 interactions with a new technique that employs LRET (luminescence resonance energy transfer). The amplitude of LRET in mixed oligomers of the haem protein labelled with donor and acceptor fluorophores exhibited a sigmoidal dependence on the surface density of CYP3A4 in Supersomes™. The addition of ANF eliminated this sigmoidal character and increased the degree of oligomerization at low enzyme concentrations. Therefore the mechanisms of CYP3A4 allostery with ANF involve effector-dependent modulation of P450–P450 interactions.

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Bartoszek, Agnieszka. "Metabolic activation of adriamycin by NADPH-cytochrome P450 reductase; overview of its biological and biochemical effects." Acta Biochimica Polonica 49, no. 2 (June 30, 2002): 323–31. http://dx.doi.org/10.18388/abp.2002_3790.

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NADPH-cytochrome P450 reductase (P450 reductase) is one of the enzymes implicated in the metabolism of adriamycin, a very important clinically used antitumour drug. However, apart from the enzyme involvement, so far little was known about the chemical route and biochemical effects of this process. We demonstrated that the application of P450 reductase simultaneously with adriamycin to tumour cells in culture significantly increased cytotoxicity of the drug. Under tissue culture conditions, we noticed also that, in the presence of P450 reductase, adriamycin metabolite(s), displaying an altered spectrum within the visible light range were formed. This observation was taken adavantage of to study the metabolism of adriamycin in cell-free systems, using initially the enzyme isolated from rat liver and the recently obtained recombinant human P450 reductase. The reductive conversion of the drug turned out to be a multi-stage process, which occurred only under aerobic conditions and was accompanied by excessive NADPH consumption. Further research carried out with the aid of radical scavengers and radiolabelled adriamycin revealed that the enhancement of biological activity of adriamycin by P450 reductase stemmed from the formation of alkylating metabolite(s) rather than from the promotion of redox cycling known to be induced in the presence of anthracyclines.

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Li, Zhong, Yuanyuan Jiang, F. Peter Guengerich, Li Ma, Shengying Li, and Wei Zhang. "Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications." Journal of Biological Chemistry 295, no. 3 (January 2020): 833–49. http://dx.doi.org/10.1016/s0021-9258(17)49939-x.

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Ajayi, Rachel Fanelwa, Ezo Nxusani, Samantha F. Douman, Anovuyo Jonnas, Priscilla Gloria Lorraine Baker, and Emmanuel Iheanyichukwu Iwuoha. "An Amperometric Cytochrome P450-2D6 Biosensor System for the Detection of the Selective Serotonin Reuptake Inhibitors (SSRIs) Paroxetine and Fluvoxamine." Journal of Nano Research 44 (November 2016): 208–28. http://dx.doi.org/10.4028/www.scientific.net/jnanor.44.208.

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Paroxetine is the second most prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant drug, characterized by extensive inter-individual variation in steady state plasma concentrations resulting in drug toxicity amongst patinets. A nanopolymeric biosensor for studying the biotransformation of paroxetine is presented. The bioelectrode system consists of cytochrome P450-2D6 enzyme encapsulated in nanotubular poly (8-anilino-1-napthalene sulphonic acid) electrochemically deposited on gold. The biosensing procedure involved the determination of the extent of modulation of fluvoxamine responses to the P450-2D6 enzyme electrode after incubation in paroxetine standard solutions. Paroxetine inhibited the activity of cytochrome P450-2D6 (CYP2D6) resulting in a decrease in the fluvoxamine signal of the biosensor. The biosensor gave a linear analytical response for the paroxetine in the interval 0.005 and 0.05 μM, with a detection limit of 0.002 μM and a response time of 30 s. Electrochemical Michaelis–Menten kinetics of the reversible competitive inhibition of the fluvoxamine responses of the biosensor by 0, 0.05 and 0.1 μM paroxetine gave apparent Michaelis–Menten constant (KMapp) values of 1.00 μM, 1.11 μM and 1.25 μM, respectively. The corresponding value for the maximum response, IMAX was 0.02 A. The dissociation constant, KI, value evaluated from Dixon analysis of the paroxetine modulation data was estimated to be-0.02 μM while Cornish-Bowden analysis confirmed the competitive inhibitory characteristics of the enzyme.

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Tennant, MD, DrPH, Forest. "Opioid regimens in patients with chronic pain with multiple cytochrome P450 defects." Journal of Opioid Management 11, no. 3 (May 1, 2015): 237. http://dx.doi.org/10.5055/jom.2015.0272.

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There is a subgroup of patients with chronic pain who have multiple cytochrome P450 enzyme defects. These patients tend to use opioids that are not metabolized by the CYP450 system and most apparently require a higher than average dosage. A significant number require nonoral administration.

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Wang, Fei, Jie Zhou, Zhoukun Li, Weiliang Dong, Ying Hou, Yan Huang, and Zhongli Cui. "Involvement of the Cytochrome P450 System EthBAD in theN-Deethoxymethylation of Acetochlor by Rhodococcus sp. Strain T3-1." Applied and Environmental Microbiology 81, no. 6 (January 16, 2015): 2182–88. http://dx.doi.org/10.1128/aem.03764-14.

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ABSTRACTAcetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)-acetamide] is a widely applied herbicide with potential carcinogenic properties.N-Deethoxymethylation is the key step in acetochlor biodegradation.N-Deethoxymethylase is a multicomponent enzyme that catalyzes the conversion of acetochlor to 2′-methyl-6′-ethyl-2-chloroacetanilide (CMEPA). Fast detection of CMEPA by a two-enzyme (N-deethoxymethylase–amide hydrolase) system was established in this research. Based on the fast detection method, a three-component enzyme was purified fromRhodococcussp. strain T3-1 using ammonium sulfate precipitation and hydrophobic interaction chromatography. The molecular masses of the components of the purified enzyme were estimated to be 45, 43, and 11 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Based on the results of peptide mass fingerprint analysis, acetochlorN-deethoxymethylase was identified as a cytochrome P450 system, composed of a cytochrome P450 oxygenase (43-kDa component; EthB), a ferredoxin (45 kDa; EthA), and a reductase (11 kDa; EthD), that is involved in the degradation of methyltert-butyl ether. The gene clusterethABCDwas cloned by PCR amplification and expressed inEscherichia coliBL21(DE3). Resting cells of a recombinantE. colistrain showed deethoxymethylation activity against acetochlor. Subcloning ofethABCDshowed thatethABDexpressed inE. coliBL21(DE3) has the activity of acetochlorN-deethoxymethylase and is capable of converting acetochlor to CMEPA.

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Hume, R., A. Burchell, BB Allan, CR Wolf, RW Kelly, A. Hallas, and B. Burchell. "The ontogeny of key endoplasmic reticulum proteins in human embryonic and fetal red blood cells." Blood 87, no. 2 (January 15, 1996): 762–70. http://dx.doi.org/10.1182/blood.v87.2.762.bloodjournal872762.

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Recently, using immunohistochemical methods, we surprisingly found that endoplasmic reticulum glucose-6-phosphatase is present in human embryonic and fetal red blood cells (RBCs) but not in adult RBCs. The fact that an endoplasmic reticulum enzyme, whose major site of expression in adults is the liver, is present in human embryonic and fetal RBCs, particularly nucleated cells, indicated that it would be sensible to determine whether these cells also contain other endoplasmic reticulum enzyme systems normally found in adult liver. Therefore, we have studied the expression of other endoplasmic reticulum proteins and found that human embryonic and fetal RBC precursors contain other protein components of the glucose-6- phosphatase system, ie, the phosphate and glucose transport proteins as well as other enzymes (eg, uridine diphosphate- glucuronosyltransferases, cytochrome P450 isozymes, nicotinamide adenine dinucleotide phosphate cytochrome P450 oxidoreductase, and prostaglandin H synthase). In addition, we also found the predominantly cytosolic markers 15-hydroxyprostaglandin dehydrogenase, prostaglandins PGE2 and 13,14-dihydro-15-keto-PGE2. The expression of key enzymes that control glucose production, detoxification of endobiotics and xenobiotics, and the regulation of prostaglandin levels in embryonic and early fetal RBCs means that these cells may have an important role in protecting the developing conceptus before it establishes an efficient circulation and before all tissues fully express their normal complement of these enzymes.

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47

Visser, Sam P. de. "Density functional theory (DFT) and combined quantum mechanical/molecular mechanics (QM/MM) studies on the oxygen activation step in nitric oxide synthase enzymes." Biochemical Society Transactions 37, no. 2 (March 20, 2009): 373–77. http://dx.doi.org/10.1042/bst0370373.

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In this review paper, we will give an overview of recent theoretical studies on the catalytic cycle(s) of NOS (nitric oxide synthase) enzymes and in particular on the later stages of these cycles where experimental work is difficult due to the short lifetime of intermediates. NOS enzymes are vital for human health and are involved in the biosynthesis of toxic nitric oxide. Despite many experimental efforts in the field, the catalytic cycle of this important enzyme is still surrounded by many unknowns and controversies. Our theoretical studies were focused on the grey zones of the catalytic cycle, where intermediates are short-lived and experimental detection is impossible. Thus combined QM/MM (quantum mechanics/molecular mechanics) as well as DFT (density functional theory) studies on NOS enzymes and active site models have established a novel mechanism of oxygen activation and the conversion of L-arginine into Nω-hydroxo-arginine. Although NOS enzymes show many structural similarities to cytochrome P450 enzymes, it has long been anticipated that therefore they should have a similar catalytic cycle where molecular oxygen binds to a haem centre and is converted into an Fe(IV)-oxo haem(+•) active species (Compound I). Compound I, however, is elusive in the cytochrome P450s as well as in NOS enzymes, but indirect experimental evidence on cytochrome P450 systems combined with theoretical modelling have shown it to be the oxidant responsible for hydroxylation reactions in cytochrome P450 enzymes. By contrast, in the first catalytic cycle of NOS it has been shown that Compound I is first reduced to Compound II before the hydroxylation of arginine. Furthermore, substrate arginine in NOS enzymes appears to have a dual function, namely first as a proton donor in the catalytic cycle to convert the ferric-superoxo into a ferric-hydroperoxo complex and secondly as the substrate that is hydroxylated in the process leading to Nω-hydroxo-arginine.

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Lewis, David, Yuko Ito, and Peter Goldfarb. "Enzyme-Substrate Binding Interaction Energies and Their Application to the Cytochrome P450 System." Current Computer Aided-Drug Design 4, no. 2 (June 1, 2008): 111–22. http://dx.doi.org/10.2174/157340908784533274.

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Mayhew, M. P., V. Reipa, M. J. Holden, and V. L. Vilker. "Improving the Cytochrome P450 Enzyme System for Electrode-Driven Biocatalysis of Styrene Epoxidation." Biotechnology Progress 16, no. 4 (August 4, 2000): 610–16. http://dx.doi.org/10.1021/bp000067q.

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Preskorn, S. "P.1.097 The clinical relevance of the cytochrome P450 enzyme system to antidepressants." European Neuropsychopharmacology 7 (September 1997): S165—S166. http://dx.doi.org/10.1016/s0924-977x(97)88546-x.

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Journal articles on the topic 'Cytochrome P450 enzyme system'

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