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Givens, Raymond Carlos Maeda Nobuyo. "Physiologic effects of cytochrome P450 3A activity." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1371.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.<br>Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition, School of Public Health." Discipline: Nutrition; Department/School: Public Health.
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Westlind, Johnsson Anna. "Pharmacogenetics of human cytochrome P450 3A (CYP3A) enzymes /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-688-x.
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Johnson, Trevor Nigel. "Developmental and pathological changes in intestinal cytochrome P450 3A." Thesis, University of Sheffield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.482841.
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Tydén, Eva. "Cytochrome P450 3A and ABC-transport proteins in horse /." Uppsala : Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 2008. http://epsilon.slu.se/200893.pdf.
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Curi, Pedrosa Rozangela. "Effet de quelques anti-secrétoires gastriques sur l'expression des cytochromes P450 1A et 3A hépatiques humains : implication des cytochromes P450 3A dans le métabolisme de l'omeprazole." Montpellier 1, 1992. http://www.theses.fr/1992MON13519.
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Engman, Helena. "Intestinal barriers to oral drug absorption : cytochrome P450 3A and ABC-transport proteins /." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3599.
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Mugundu, Ganesh. "Pharmacogenetic Impact on Metabolism and Cytochrome P450 (CYP)3A Inductive Effect of Tamoxifen." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1266596002.
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Zerilli, Alain. "Cytochromes P450 2E1 et 3A : spécificité de l'induction tissulaire chez le rat, spécificité des substrats du P450 2E1." Brest, 1997. http://www.theses.fr/1997BRES3102.
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Swales, Karen Elizabeth. "An investigation of host cell effects on the xenobiotic induction of cytochrome P450 3A." Thesis, University of Surrey, 2002. http://epubs.surrey.ac.uk/843184/.
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Species differences exist in the induction response of CYP3A genes to xenobiotics, and these are proposed to be due, in part, to host cell differences. These host cell effects were investigated functionally by trans-species transfections of alkaline phosphatase reporter genes containing ~1.5 kb of the CYP3A23 or CYP3A4 5' flanking regions into human HepG2 and rat FaO and H4IIEC3 hepatoma cells. HepG2 and FaO cells were demonstrated to support induction of the activity of both CYP3A constructs by 50 muM dexamethasone but H4IIEC3 cells could not. The receptor mRNA complement (CAR, GRa, HNF4a, PXR and RXRa) of the rat and human cell lines were characterised in comparison to rat and human liver using semi-quantitative RT-PCR to identify any differences. Principal component analysis (PCA) of the receptor mRNA levels was scattered indicating that rat liver does not resemble human liver and that hepatoma cell lines do not resemble their liver counterparts in terms of individual receptor mRNA levels. Increasing knowledge of nuclear receptor interactions with response elements led to consideration that response to xenobiotics may be due to relative receptor abundance in the cells, as opposed to individual receptor expression levels. PCA on comparison ratios showed clustering of human and HepG2 receptor ratios, supporting the observation that CYP3A reporter gene induction responses in HepG2 cells mimic those in vivo. From this data we hypothesise that relative receptor expression levels are key to determining CYP3A responsiveness to xenobiotics. However this hypothesis could not be further examined at the protein level, as Western blotting experiments were equivocal. The latter hypothesis was further examined through the use of TaqMan, expanding the receptor cohort to include COUPTFI and RXRs and gamma, plus CYP3A mRNA expression levels. In addition the effects of xenobiotics, dexamethasone, rifampicin, PCN and phenobarbital at a range of concentrations, were tested. The hepatoma cell lines did not have the same endogenous CYP3A mRNA expression or induction profiles as liver. The TaqMan results suggested that in human CYP3A regulation, the relative abundance of PXR heterodimerisation partners or accessory factors were more important than the level of PXR, whereas in rats, PXR was dominant in determining induction of CYP3A, indicating a further species difference. In conclusion, host cell effects on CYP3A regulation are dependent on receptor abundance and interactions, as well as differential receptor activation.
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Salphati, Laurent. "P-glycoproteine et cytochrome p450 3a : interactions potentielles et roles complementaires dans l'absorption et la disposition des drogues." Paris 11, 1998. http://www.theses.fr/1998PA114805.
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Sachdeva, Karuna. "Regulation of cytochrome P450-3A (CYP3A) and pregnane X receptor (PXR) : implications to drug-drug interactions /." View online ; access limited to URI, 2005. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3186919.
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LE, BRICQUIR YANN. "Effet de l'interferon alpha sur les cytochromes p-450 1a2 et 3a chez les malades atteints d'hepatite chronique virale c." Montpellier 1, 1993. http://www.theses.fr/1993MON11150.
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NALLANI, CHAKRAVARTHULA SRIKANTH. "DIFFERENTIAL INDUCTION OF HEPATIC CYTOCHROME P450 3A ENZYMES(S) BY TAXANE ANTICANCER AGENTS: MOLECULAR MECHANISMS AND CLINICAL IMPLICATIONS." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022623309.
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Fakhoury, May. "Pharmacogénétique en pédiatrie : 1-Expression du complexe CYP3A/P-gp dans l'entérocyte humain : 2-Implications des polymorphismes pharmacogénétiques dans la prise en charge des leucémies aiguës lymphoblastiques." Paris 5, 2005. http://www.theses.fr/2005PA05P625.
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La variabilité interindividuelle dans la biodisponibilité des médicaments est principalement due à l'âge et aux polymorphismes pharmacogénétiques. A- Projet de pharmacologie fondamentale portant sur l'expression du CYP3A/P-gp dans le duodénum humain : - au cours du développement (localisation et ARNm - lors d'une inflammation systémique (maladie de Crohn). B- Projet de pharmacologie clinique et pharmacogénétique chez les enfants atteints de leucémie aigue lymphoblastique (LAL) : - évaluation de la variabilité de l'activité de la thiopurine S-méthyltransférase (TPMT) en cours de traitement de maintenance - estimation des paramètres pharmacocinétiques de population du méthotrexate (MTX) et sélection d'un modèle prédictif avec 2 prélèvements (H24 et H48) - impact des polymorphismes génétiques (enzymes de métabolisme et protéines de transport des anticancéreux) sur la survenue d'effets indésirables: résultats préliminaires obtenus à l'hôpital Robert Debré (France) et Hôtel Dieu de France (Beyrouth)<br>Xenobiotic disposition in the organism is highly variable among individuals and due to the impact of age and pharmacogenetic polymorphisms. A- Fundamental pharmacology project concerning the expression of CYP3A/P-gp complex in the human duodenum : - throughout post-natal development (localization and mRNA expression) - during systemic inflammation (Crohn's disease). Clinical pharmacology and pharmacogenetic project in children with acute lymphoblastic leukemia (LAL) : - evaluation of the variability in thiopurine S-methyltransferase (TPMT) during maintenance therapy - estimation of the pharmacokinetic parameters of methotrexate (MTX) and the proposal of a limited sampling strategy (H24 and H48) - impact of genetic polymorphisms (metabolic enzymes and transport proteins of anti-neoplasic agents) on the occurrence of side effects: preliminary results of two hospitals, Robert Debré (France) and Hôtel-Dieu de France (Beirut)
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Drocourt, Lionel. "Régulation de l'expression des cytochromes P450 des sous-familles 2B, 2C et 3A dans l'hépatocyte humain : rôles physiologiques et pharmacologiques des récepteurs nucléaires GR, PXR, et VDR." Montpellier 2, 2001. http://www.theses.fr/2001MON20203.
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Matsubayashi, Keiko. "Contribution of cytochrome P450 3A pathway to bromocriptine metabolism and effects of ferrous iron and hypoxia-reoxygenation on its elimination in the perfused rat liver." Kyoto University, 1997. http://hdl.handle.net/2433/202219.
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COSTET, PHILIPPE. "Utilisation des techniques de transgenese : analyse du phenotype murin deficient en recepteur nucleaire pparalpha et elaboration d'une lignee murine transgenique de surexpression du cytochrome p450 3a bovin." Toulouse 3, 1999. http://www.theses.fr/1999TOU30016.
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Dans le cadre de l'etude d'un modele d'invalidation d'un gene (ou knock-out), nous nous sommes interesse a la lignee murine deficiente en un recepteur nucleaire, ppar (peroxysome proliferator activated receptor). Ce recepteur, d'expression essentiellement hepatique et renale, relaie la reponse aux normolipemiants tels les fibrates et participe au metabolisme des lipides. Il est implique dans des processus toxicologiques dont la carcinogenese induite chez les rongeurs par les proliferateurs de peroxysomes, par exemple les fibrates. Une premiere etude porte sur la regulation negative des transaminases hepatiques en reponse a un traitement par des fibrates. Nous montrons que ce processus est dependant de ppar et non lie a une toxicite hepatique. Une seconde etude evalue les capacites d'activation du dimere ppar-rxr (retinoid x receptor) par un nouvel agoniste du recepteur rxr. Les trois dernieres etudes sont une evaluation physiologique du modele. Nous precisons le role de ppar dans des processus physiopathologiques (jeune et diabete) puis etudions, chez les animaux deficients, le developpement spontane et tardif d'une obesite avec dimorphisme sexuel et alteration de l'homeostasie du glucose (hypoglycemie constitutive). Nous avons parallelement entrepris un projet de lignee murine surexprimant le cytochrome p450 3a bovin (bcyp3a) dans le foie. Les p450s sont des enzymes de biotransformation impliquees dans de nombreux processus physiologiques ou de toxicite-detoxication. Dans l'objectif de la securite alimentaire, notre laboratoire souhaite developper une lignee murine de surexpression de bcyp3a, dont le panel de substrats tres large et la modulation de l'expression peuvent conduire a l'activation de molecules ou a la production de residus dans la viande et le lait. Nous presentons les differentes etapes techniques realisees pour etablir cette lignee et l'avancee de nos travaux concernant sa caracterisation.
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Cavelier, Adeline. "Complementarité des protéines de detoxication et trafic intracellulaire." Phd thesis, Université René Descartes - Paris V, 2007. http://tel.archives-ouvertes.fr/tel-00553511.
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La coopération fonctionnelle entre le cytochrome P450 3A (CYP3A) et la P-glycoprotéine (P-gp) décrite dans la littérature est un facteur déterminant contribuant à la variabilité de la biodisponibilité de la plupart des médicaments administrés per os. Le CYP3A et la P-gp sont des protéines membranaires dont les localisations respectives communément attribuées sont la membrane du réticulum endoplasmique pour le CYP3A et la membrane plasmique pour la P-gp. Le but de notre étude était une description intégrée au niveau cellulaire du fonctionnement de ces protéines membranaires de détoxication des médicaments et de leurs métabolites, grâce à la détermination de la localisation cellulaire de ces protéines par immunomarquage et par suivi fonctionnel de composés fluorescents, à l'aide de techniques de microscopie à épifluorescence. Le matériel utilisé comprenait des coupes de foie de rat et humain, des hépatocytes en culture primaire ou des lignées cellulaires de fibroblastes de Hamster chinois D/ADX surexprimant la P-gp. Nous avons ainsi démontré que le CYP3A se localise exclusivement au niveau du réticulum endoplasmique, alors que la P-gp est retrouvée au pôle apical des hépatocytes, au niveau des canalicules biliaires et sur la membrane plasmique des fibroblastes. Une colocalisation membranaire des composés et enzymes, synonyme d'une grande efficacité de détoxication, n'a pas été mise en évidence dans les hépatocytes, à cause de difficultés techniques et d'une trop faible fluorescence des substrats utilisés.
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Born, Stephanie Lynn 1968. "Characterization of canine cytochromes P450 2B and 3A." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/290587.
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The objective of these studies was to functionally characterize canine cytochromes P450 from subfamilies 2B and 3A. Studies of the canine hepatic 2B form PBD-2 had previously revealed that this enzyme exhibits a species specific ability to metabolize 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB) and catalyze progesterone 21-hydroxylation. Expression of the putative PBD-2 cDNA, 2B11, in three different heterologous systems revealed that the recombinant enzymes' apparent substrate specificities varied based upon the expression system. 2B11 expressed in COS cells and yeast did not metabolize progesterone in a manner consistent with that of the purified hepatic enzyme, suggesting that 2B11 did not encode PBD-2. However, subsequent expression of 2B11 in E. coli confirmed that this recombinant enzyme did metabolize progesterone into 21- and 16α-hydroxyprogesterone. The structural determinants of 2B11-mediated progesterone 21-hydroxylation were then examined via site-directed mutagenesis of amino acid residues 114, 290, 363, and 365. Consistent with the importance of these residues in androstenedione and 245-HCB metabolism, amino acid alterations Val 114 $\to$ Ile, Asp-290 → Ile, and Ile-363 → Val each decreased 2B11 progesterone 21-hydroxylation. 2B11 mutants at position 365 differed in their regioselective metabolism of progesterone, whereas these mutations had little affect on the stereoselective metabolism of androstenedione. Cytochrome P450 3A forms are of intense interest due to the wide range of therapeutic compounds metabolized by these enzymes. To determine if canine liver contained multiple 3A forms which exhibit substrate specificities similar to those of other species, the canine 3A form PBD-1 (3A12) was expressed in E. coli. 3A12, rabbit 3A6 and human 3A4 metabolized steroids and macrolide antibiotics into the same products at comparable rates. A 3-fold difference in the rate of troleandomycin demethylation between liver microsomes and 3A12, the identification of a novel putative 3A hepatic protein via NH₂-terminal sequencing, and isolation of a distinct 3A cDNA provided evidence for 3A multiplicity in canine liver microsomes. The identification of functionally distinct canine 3A forms could provide the framework for structure-function analysis of these clinically important enzymes. Furthermore, 3A multiplicity and the conservation of substrate specificity between canine and human forms suggests that the canine may be an appropriate model of human 3A metabolism.
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Samer, Caroline F. "Impact des cytochromes P450 2D6 et 3A sur les paramètres pharmacocinétiques et pharmacodynamiques de l'oxycodone /." Genève : Ed. Médecine et hygiène, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253454.
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Denk, Annette. "Der Effekt von Ursodeoxycholsäure auf den Cytochrom P450 3A-Metabolismus bei primär biliärer Zirrhose und gesunden Probanden." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-44811.
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"Physiologic effects of cytochrome P450 3A activity." THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, 2008. http://pqdtopen.proquest.com/#viewpdf?dispub=3289052.
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Lee, Su-Jun. "Cytochrome P450 3A forms in rainbow trout (Oncorhynchus mykiss)." Thesis, 2001. http://hdl.handle.net/1957/33090.
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Wonganan, Piyanuch. "A mechanistic study of how adenovirus infection alters the expression and function of hepatic cytochrome P450 3A." Thesis, 2010. http://hdl.handle.net/2152/ETD-UT-2010-08-1969.
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Recombinant adenoviruses, commonly used in gene therapy and vaccine applications, compromise the expression and function of hepatic CYP3A for 14 days. When given with docetaxel (DTX), plasma clearance of DTX (3.38 ± 0.22 l/kg.h) was significantly lower than those given DTX alone (6.41 ± 1.10 l/kg.h). The area under the plasma concentration-time curve of DTX in rats given virus (2,987.37 ± 197.97 ng/ml.h) was significantly greater than those given drug alone (1,666.59 ± 317.04 ng/ml.h). The virus extended the half-life of DTX three-fold. This may explain why adenoviral vectors improve chemotherapy. PEGylation of the virus reduced interleukin-6 (IL-6), IL-12, tumor necrosis factor alpha (TNF-α), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels in mice and non-human primates. PEGylation dramatically reduced transduction efficiency of virus in the baboon liver and did not alter hepatic transgene expression in the mouse. Unmodified and PEGylated virus (3 x 1012 vp/kg) reduced hepatic CYP3A4 protein by 60% and 40%, respectively 96 hours after virus administration. Catalytic activity was decreased by 55% and 45% with respect to an untreated control by the native and PEGylated viruses respectively. This suggests that changes in hepatic CYP3A during infection is not entirely due to the immune response and these observed effects most likely occur in humans. The effects of adenovirus on hepatic CYP3A expression and function in mice, however, resolved at a faster rate than that in baboons. HC-04 cells are a suitable in vitro model to study virus infection and hepatic CYP3A function. A panel of adenoviruses inhibited CYP3A catalytic activity and induced changes in expression and distribution of retinoid X receptor alpha (RXRα), pregnane X receptor (PXR) and constitutive androstane (CAR) receptors. Virus (1.5 x 1011 vp) inhibited CYP3A in the mouse. When the ability of the virus to bind to integrins was removed, changes in CYP were not detected. Treatment with a RGD peptide, that binds to integrins, reduced CYP3A activity in a manner similar to the virus. Silencing of β3 and β5 integrins also resolved changes in CYP3A activity during infection, suggesting that simple engagement of integrin receptors can initiate changes in CYP3A.<br>text
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"Assessment of cytochrome P450 3A activity and relationship to response to statin therapy." 2013. http://library.cuhk.edu.hk/record=b5884361.
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Xiao, Yajie.<br>Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.<br>Includes bibliographical references (leaves 156-190).<br>Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.<br>Abstract also in Chinese.
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Jian, Wen-Chi, and 簡文琪. "Gender-and Age-Related Changes in Territrems Metabolism by Cytochrome P450 3A family in Rat Liver Microsomes." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/37733821266465215242.
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碩士<br>國立臺灣大學<br>毒理學研究所<br>91<br>Three tremogenic mycotoxines, designated as territrem A, B and C (TRA, TRB and TRC) were isolated from a chloroform extract of rice culture of Aspergillus terreus 23-1.The metabolism of TRA in liver microsomes of adult male and female rats have been studied. Three metabolites of TRA were formed by three sequential oxidative steps in male rats. There are first, hydroxylation at the 4b-C methyl group of TRA to form MA1; second, oxidation at 4b-C hydroxyl group of MA1 to form MAX; and third, decarbonylation at the 4b-C oxo group of MAX to form MA2. However, in female only MA1 was formed from TRA. Further, studies of cytochrome P450 isforms catalyzing TRA metabolism revealed that MA1 formation is catalyzed by both CYP3A1 and CYP3A2, while the formation of MAX and MA2 are catalyzed by CYP3A2. The sex difference of both amounts of protein and mRNA of CYP3A1/2 expression and territrems metabolism were examined in the present study.
Many studies concerning age-related changes in CYP450 linked to metabolism of xenobiotics and drug have been reported. Therefore, next study of CYP3A1 and CYP3A2 related to age and sex hormone are our major concern.
In the present studies, the following results were obtained: (1)Both protein and mRNA of CYP3A1 are constitutively expressed in both gender at 2- to 76-week-old age. (2)The protein levels and mRNA of CYP3A2 constitutively expressed in 2- to 52-week-old male rats, but they decreased after 76-week-old age, and decreased in female rat when after 6-week-old. (3)The expression of CYP3A1 or CYP3A2 in male rats are generally higher than female rats. (4)Formation of the different metabolites was due to change of aromatic moiety of territrems. (5)Formation of MAX and MA2 decreased after 52-week-old male rats and ceased after 6-week-old female rats. (6)The amount of MB2 formed in female rats was less than in male rats, but the amount of MB1 (TRC metabolites) formed in female rats was higher than male rats. (7)The protein levels of CYP3A2, production of MAX and MA2 were restored by administration on high dose testosterone (750 mg) in the castrated male rats.
Therefore, it is concluded that: (1) The metabolism of TRA have sexual difference were related to the protein and mRNA expression of CYP3A2. The different metabolites formed could be due to the modification of the chemical structure of the aromatic moiety of territrems. The protein levels and mRNA expression of CYP3A2 and efficiency of territrems metabolism were decreased after 76-week-old that cause feminization at elder age of male rats. (2)Testosterone status modulated CYP3A2 expression and caused sex differenced of metabolism. For instances, serum level of testosterone decreased after aging and then changed territrems metabolism efficiency. In conclusion, age- and gender-related changes on territrems metabolism were due to CYP3A2 expression which regulated by testosterone.
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Lin, Yu-Hsuan, та 林侑璇. "1.Inhibition Study of Territrem 4β-C hydroxylation and O-demethylation by Seven Human Cytochrome P450 3A4 substrates;2.Application of the Relative Activity Factor to Approach the Role of Cytochrome P450 3A to the Metabolism of Territrems by Wistar Rats a". Thesis, 2007. http://ndltd.ncl.edu.tw/handle/16537366566039898879.
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碩士<br>國立臺灣大學<br>毒理學研究所<br>95<br>1. Inhibition Study of Territrem 4β-C hydroxylation and O-demethylation by Seven Human Cytochrome P450 3A4 substrates
Territrems are the structure related tremogenic mycotoxins, which are produced by Aspergillus terreus 23-1. Previous research indicated that MA1 can be produced from TRA hydroxylation, and TRB can produce MB2 and MB4 by 4β-C hydroxylation and O-demethylation. These reactions are mainly catalyzed by P450 3A4 in liver.
Structure of CYP3A4 contains great active site, and also capable of binding of more than two substrates. Interactions between substrates cause the kinetics of CYP3A4 become atypical. In addition, some amino acids in CYP3A4 active site plays an important role in substrate binding.
To understand the relations of the location of TRA and TRB metabolism, this experience uses cell line V79MZh3A4 which expressing human CYP3A4. We provide TRA and TRB in time to metabolize and analyze the metabolite by HPLC. Double reciprocal plot facilitates understanding of types of inhibition.
Results shows that in the process of TRA producing MA1 and TRB producing MB2, TRB and TRA are mutually mixed-type inhibition. In the process of TRB producing MB4, TRB and TRA are un-competitive inhibition.
To delve more into the combinational location of TRB on CYP3A4, select seven kinds of CYP3A4 substrates to metabolize with TRB at the same time, in order to indirectly infer the location of TRB on CYP3A4. The results presents that in the metabolizing process from TRB to MB2, inhibition occurs with testosterone and un-inhibition occurs with budesonide. Also, in the metabolizing process of TRB to MB4, un-competitive inhibition occurs with testosterone, etoposide and mixed-type inhibition occurs with budesonide.
Inferring from above, combination of TRA and TRB on CYP3A4 have different location, but one combination of another might change the structural location, causing declines affinity of CYP3A4.
Additionally, by predicting the competitive locations of TRB and testosterone, we suggest that TRB can form a hydrogen bond with serine-119 in CYP 3A4 active site. But above inhibitors locate differently, and they only interact with each other. About the modes of TRB and substrate, it still remains unknown. Moreover, our experiment observed many atypical characteristics of CYP3A4, proving the complexity of CYP3A4.
2.Application of the Relative Activity Factor to Approach the Role of Cytochrome P450 3A to the Metabolism of Territrems by Wistar Rats and Human Liver Microsomes
Cytochrome P450 is the most crucial oxidative enzyme system responsible for metabolizing over 90% endogenous and xenobiotics in human. Its prevalent characteristics of substrate specificity often result in interactions between substrates and, moreover, two or more CYP enzymes often contribute to the metabolism of a single drug. Due to above reasons, it’s important to determine the relative contribution of each CYP to net metabolism of the drug..
The concept of RAF (relative activity factor) was first proposed by Crespi at 1995. The RAF approach has been applied successfully to estimate CYP isoforms contribution to drug metabolism.
According to the previous research in our Laboratory, during metabolism of TRB to MB2, CYP3A4 was major involving enzyme, containing 97.1%: during metabolism of TRB to MB4, CYP3A4 was the major, containing 64.3%.
To clarify further the relative contributions of each CYP isoforms to the metabolism of TRA and TRB, we use rP450s and different ages and genders of human, and Wistar rats, and calculate the RAF.
Experiment results indicated that during metabolism of TRA to MA1 in rat and human liver microsomes, CYP3A2 (84.7%) and CYP3A4 (85.9%) are major involving enzyme. During metabolism of TRB to MB2 and MB4 in rat liver microsomes, CYP3A1 (92%) and CYP3A2 (65.2%) are major involving enzyme.
Furthermore, the results indicated that comparing the sex and age differences, 8-week-old male rats presented best results in the process of metabolism. But for human bodies, there is no obvious correlation between age and sex. Many factors might explain this, including the chemical structure of TRA and TRB, the mRNA and protein expression level of CYP3A1/2 in rats, the expression level and activity of CYP3A4/5 in different human bodies, amino acid sequence homology between CYP3A1/2 and CYP3A4/5, and the substrate binding sites in CYPs.
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Jelínková, Sandra. "Vliv vandetanibu, lenvatinibu a ellipticinu na expresi potkaních cytochromů P450 1A a 3A." Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-379348.
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In recent years, the inhibiition of tyrosine kinases,which may incorrectly regulate some singaling pathway has been used to treat cancer as so-called biological therapy. An example of such inhibitors are vandetanib and lenvatinib. These two substances are used to treat thyroid gland tumors because they affect vascular growth factor receptor or endothelial growth factor receptor that can regulate tumor growth and metastasis. Ellipticine, which has anti-tumor effects on lots of tumor disease, has been investigated in this study together with vandetanib and lenvatinib. In this diploma thesis, the effect of mentioned tyrosine kinase inhibitors, ellipticine and their combinations on gene and protein expression of CYP1A1, 1A2, 3A1 and 3A2 in rat liver in vivo was determined. Protein expression was studied using Western blot method with imunodetection. Gene expression was assessed by quantitative PCR. Moreover, the effect of tested substances and their combinations on CYP1A activity (measured as 7-ethoxyresorufin O-deethylation), CYP1A2 activity (measured as 7-methoxyresorufin O-demethylation), CYP1A1 activity (measured as Sudan I oxidation), CYP3A specific activity (measured as testosteron 6β-hydroxylation) and ellipticine, vandetanib, lenvatinib metabolism was determined. It has been confirmed that...
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Svobodová, Lucie. "Oxidace protinádorového léčiva ellipticinu cytochromy P450 3A a 2B." Master's thesis, 2007. http://www.nusl.cz/ntk/nusl-374387.
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Chen, Pei-Chun, and 陳佩君. "The role of cytochrome P450 3A in the metabolism of Territrem B and C in Liver microsomes from 14-week-old Wistar rats；The effect of sex hormone and xenobiotics on CYP450 3A1/2 expression in rat hepatoma cells McA-RH8994 and McA-RH7777." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/27384862665791448128.
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碩士<br>國立臺灣大學<br>毒理學研究所<br>92<br>第一章
Territrem is a tremogenic mycotoxin isolated from the chloroform extracts of rice culture of Aspergillus terreus 23-1. The previous study showed that three metabolites MA1, MAX and MA2 of territrem A (TRA) were formed in male rats, and gender difference in TRA metabolism of Wistar rats from that only MA1 formation was formed in female rats. Further study of cytochrome P450 involvement TRA metabolism suggested CYP3A1 is mainly responsible for MA1 formation and CYP3A2 is responsible for MA1, MAX, and MA2 formation. It has been reported that four metabolites of territrem B (TRB), designated as MB1, MB2, MB3, and MB4 and one metabolite of territrm C (TRC), designated as MB1, were formed from liver microsomes of both sexs Wistar rats. The metabolism of TRB and TRC related to gender difference and CYP450 family involved were not investigated.
To investigate which cytochrome P450 isoforms were involved in TRB and TRC metabolism, four CYP450 isoform-specific inhibitors (
furafylline, orphenadrine, cimetidine, and troleandomycin) and antibodies against CYP1A2, CYP2B1, CYP2C11, or CYP3A2 were used. The gender difference in TRB and TRC metabolism in liver microsomes of 14-week-old male and female Wistar rats were also investigated. The following results indicated that (1) Metabolism of TRB to MB2, and metabolism of TRC to MB1 were observed in both sexes. The amounts of MB2, MB4, and MB1 formed were higher in male rats.(2) Formation of MB2, MB4, and MB1 was markedly inhibited by cimetidine and troleandomycin, but less by furafylline and orphenadrine. (3) Anti-CYP3A2 antibody markedly inhibited MB2, MB4, and MB1 formation, while antibodies against CYP1A1, CYP2B1, or CYP2C11 had little effect, and (4) Of the seven tested supersomes from baculovirus-transformed insect cells expressing rat CYP450 isoforms ( 1A1, 1A2, 2B1, 2C11, 2C12, 3A1, and 3A2), only those expressing CYP3A1 and CYP3A2 metabolized TRB and TRC. (5) The amounts of MB2, MB4, and MB1 were related to the 6��-testosterone hydroxylase activity and CYP3A1/2 protein content. (6) Immunoblotting showed that CYP3A1 was expressed in both sexes, but at different levels, while CYP3A2 was only expressed in male. These results suggest that the formation of MB2, MB4, and MB1 in liver microsomes from 14-week-old rats of either sex is mediated by CYP3A1 and CYP3A2.
第二章
Cytochrome P450s constitute a multigene family of hemoproteins responsible for the metabolism of numerous xenobiotics, including therapeutic drugs, environmental chemicals, and dietary constituents, as well as such endogenous compounds as steroid and bile acids. Among them, CYP3A enzymes are the most abundant P450 enzymes and involved two thirds of xenobiotics. In the rat exists as two isoenzymes, CYP3A1 and CYP3A2. The protein level of CYP3A2 was expressed in 20-day-old rat of both genders, constitutively expressed in male rats, but decreased after puberty in female rats and extinguished in the adult female. Previous studies showed that (1) the sex difference in TRA metabolism was observed. (2) CYP3A1 and CYP3A2 are mainly responsible for TRA metabolism. (3) Treatment of Wistar rats with either dexamethasone (DEX) or Phenobarbital (PB) markedly increased in CTP3A protein level . Whereas, a similar rise in the metabolism of TRA. (4) In the gonadectomized male rats, MAX and MA2 formation were reversed when the animals were further treated by testosterone. Whereas, CYP3A2 protein levels was reversed by further testosterone treatment with gonadectomized male rats.
Therefore it suggested that testosterone may regulate CYP3A2 gene expression. For this purpose, two cultured cell lines, called McA-RH8994 and McA-RH7777, were established from rat hepatoma cells by in vitro culture with cytochrome P450 inducer, such as DEX and PB, and sex hormone, such as dihydrotestosterone (DHT) and ���{estradiol investigated protein levels, mRNA, and transcription factors responsible for CYP3A1 and CYP3A2. Whereas, it was also investigated 6��-testosterone hydroxylase activity and the metabolism of TRA in these two cell lines..
In the present study, the following results were obtained : (1) CYP3A1 mRNA and protein level are increased by DEX and PB 72 hr treatment. (2) Only MA1 formed from TRA by DEX treatmentthe. (3) 6β-hydroxytestosterone formation was higher in DEX and PB treatment. (4) For nuclear transcription factor of CYP3A, PXR/RXR�� mRNA and protein level are increased by DEX treatment, the protein level of glucocorticoid receptor (GR) was markedly decreased, and the protein levels of androgen receptor (AR) was not changed.
These results suggest that (1) In vitro cell culture, CYP3A1 was markedly induced by xenobiotics, while endogenous, such as sex hormone, may be indirectly regulated CYP3A2 gene expression. (2) DEX induce CYP3A1 level through PXR/RXR?rather than protypical GR pathway.
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Fenneteau, Frédérique. "Prédiction des impacts pharmacocinétiques des interactions médicamenteuses impliquant des CYP3A et les glycoprotéines-P : développement de modèles physiologiques et analyse de sensibilité." Thèse, 2009. http://hdl.handle.net/1866/3563.
Full textAbstract:
Les propriétés pharmacocinétiques d’un nouveau médicament et les risques d’interactions médicamenteuses doivent être investigués très tôt dans le processus de recherche et développement. L’objectif principal de cette thèse était de concevoir des approches prédictives de modélisation du devenir du médicament dans l’organisme en présence et en absence de modulation d’activité métabolique et de transport.
Le premier volet de recherche consistait à intégrer dans un modèle pharmacocinétique à base physiologique (PBPK), le transport d’efflux membranaire gouverné par les glycoprotéines-P (P-gp) dans le cœur et le cerveau. Cette approche, basée sur des extrapolations in vitro-in vivo, a permis de prédire la distribution tissulaire de la dompéridone chez des souris normales et des souris déficientes pour les gènes codant pour la P-gp. Le modèle a confirmé le rôle protecteur des P-gp au niveau cérébral, et a suggéré un rôle négligeable des P-gp dans la distribution tissulaire cardiaque pour la dompéridone.
Le deuxième volet de cette recherche était de procéder à l’analyse de sensibilité globale (ASG) du modèle PBPK précédemment développé, afin d’identifier les paramètres importants impliqués dans la variabilité des prédictions, tout en tenant compte des corrélations entre les paramètres physiologiques. Les paramètres importants ont été identifiés et étaient principalement les paramètres limitants des mécanismes de transport à travers la membrane capillaire.
Le dernier volet du projet doctoral consistait à développer un modèle PBPK apte à prédire les profils plasmatiques et paramètres pharmacocinétiques de substrats de CYP3A administrés par voie orale à des volontaires sains, et de quantifier l’impact d’interactions médicamenteuses métaboliques (IMM) sur la pharmacocinétique de ces substrats. Les prédictions des profils plasmatiques et des paramètres pharmacocinétiques des substrats des CYP3A ont été très comparables à ceux mesurés lors d’études cliniques. Quelques écarts ont été observés entre les prédictions et les profils plasmatiques cliniques mesurés lors d’IMM. Cependant, l’impact de ces inhibitions sur les paramètres pharmacocinétiques des substrats étudiés et l’effet inhibiteur des furanocoumarins contenus dans le jus de pamplemousse ont été prédits dans un intervalle d’erreur très acceptable.
Ces travaux ont contribué à démontrer la capacité des modèles PBPK à prédire les impacts pharmacocinétiques des interactions médicamenteuses avec une précision acceptable et prometteuse.<br>Early knowledge of pharmacokinetic properties of a new drug candidate and good characterization of the impact of drug-drug interaction (DDI) on those properties is of crucial importance in the process of drug research and development. The main objective of this thesis consisted in the conception of PBPK models able to predict the drug disposition in the absence and presence of metabolic and transport activity modulation.
The first part of this work aimed to develop a PBPK model that incorporates the efflux function of P-gp expressed in various tissues, in order to predict the impact of P-gp activity modulation on drug distribution. This approach, based on in vivo-in vitro extrapolation for estimating the transport-related parameters, allowed the prediction of domperidone distribution in heart and brain of wild-type mice and P-gp deficient mice. The model pointed out the protective function of P-gp in brain whereas it showed the negligible protective effect of P-gp in heart.
The second part of the project aimed to perform the global sensitivity analysis of the previous PBPK model, in order to investigate how the uncertainly and variability of the correlated physiological parameters influence the outcome of the drug distribution process. While a moderate variability of the model predictions was observed, this analysis confirmed the importance for a better quantitative characterization of parameters related to the transport processes trough the blood-tissue membrane. Accounting for the input correlation allowed the delineation of the true contribution of each input to the variability of the model outcome.
The last part of the project consisted in predicting the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human, alone or with an inhibitor. Successful predictions were obtained for a single administration of the CYP3A substrates. Some deviations were observed between the predictions and in vivo plasma profiles in the presence of DDI. However, the impact of inhibition on the PK parameters of the selected substrates and the impact of grapefruit juice-mediated inhibition on the extent of intestinal pre-systemic elimination were predicted within a very acceptable error range.
Overall, this thesis demonstrated the ability of PBPK models to predict DDI with promising accuracy.
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Denk, Annette Carola [Verfasser]. "Der Effekt von Ursodeoxycholsäure auf den Cytochrom-P450-3A-Metabolismus bei primär biliärer Zirrhose und gesunden Probanden / vorgelegt von Annette Carola Denk." 2005. http://d-nb.info/977662837/34.
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