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1

Heywood, R. "The toxicology of gossypol acetic acid and (−)-gossypol." Contraception 37, no. 2 (1988): 185–90. http://dx.doi.org/10.1016/0010-7824(88)90129-1.

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2

Hong, C. Y., J. J. Huang, and P. Wu. "The Inhibitory Effect of Gossypol on Human Sperm Motility: Relationship with Time, Temperature and Concentration." Human Toxicology 8, no. 1 (1989): 49–51. http://dx.doi.org/10.1177/096032718900800109.

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The inhibitory effect of gossypol acetic acid on human sperm motility was studied with a transmembrane migration method. Gossypol decreased sperm motility after it had been incubated with semen for more than 15 min. However, when sperm motility was evaluated immediately after semen had been mixed with gossypol, no inhibitory effect could be found. We consider that the sperm immobilizing potency of gossypol is much less than our previously studied sperm immobilizing agents. It is unlikely that gossypol can be developed as a vaginal spermicide. The importance of time course in the pharmacologica
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3

Kitada, Shinichi, Christina L. Kress, Maryla Krajewska, Lee Jia, Maurizio Pellecchia, and John C. Reed. "Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)." Blood 111, no. 6 (2008): 3211–19. http://dx.doi.org/10.1182/blood-2007-09-113647.

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Abstract Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apo-gossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of g
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4

Daneshmand, Mahsa, Jamileh Salar Amoli, and Tahereh Ali Esfahani. "A Comparative Study of the Cytotoxic Effects and Oxidative Stress of Gossypol on Bovine Kidney and HeLa Cell Lines." Iranian Journal of Toxicology 15, no. 3 (2021): 157–64. http://dx.doi.org/10.32598/ijt.15.3.795.1.

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Background: Cotton seed is one of the main sources of protein in animal feeds, containing gossypol, which has been shown to have toxic effects. Results reported by various studies also indicate the anti-cancer effects of gossypol on various cell types. However, its toxic effects on human and animal cells have not been fully established. This study was planned to investigate, for the first time, the cytotoxic effects and oxidative stress induced by gossypol on normal Bovine Kidney (BK) and HeLa cell lines, representing typical healthy and cancer cells, respectively. Methods: The BK and HeLa cel
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5

Wang, Wei-Kang, Yan-Lu Wang, Wen-Juan Li, Qi-Chao Wu, Sheng-Li Li, and Hong-Jian Yang. "Gossypol Exhibited Higher Detrimental Effect on Ruminal Fermentation Characteristics of Low-Forage in Comparison with High-Forage Mixed Feeds." Toxics 9, no. 3 (2021): 51. http://dx.doi.org/10.3390/toxics9030051.

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Gossypol is a key anti-nutritional factor which limits the feeding application of cottonseed by-products in animal production. A 2 × 4 factorial in vitro experiment was conducted to determine the effect of gossypol addition levels of 0, 0.25, 0.5, and 0.75 mg/g on ruminal fermentation of a high-forage feed (HF, Chinese wildrye hay/corn meal = 3:2) in comparison with a low-forage feed (LF, Chinese wildrye hay/corn meal = 2:3). After 48 h of incubation, in vitro dry matter disappearance was greater in the LF than the HF group, while the cumulative gas production and asymptotic gas production wer
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6

Beaudoin, Allan R. "The embryotoxicity of gossypol." Teratology 32, no. 2 (1985): 251–57. http://dx.doi.org/10.1002/tera.1420320213.

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7

de Peyster, Ann, and Yi Y. Wang. "Genetic toxicity studies of gossypol." Mutation Research/Reviews in Genetic Toxicology 297, no. 3 (1993): 293–312. http://dx.doi.org/10.1016/0165-1110(93)90021-e.

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8

Kitada, Shinichi, Lee Jia, Lori C. Coward, et al. "Bcl-2 Antagonist ApoGossypol (NSC736630) Displays Single-Agent Activity in Bcl-2 Transgenic Mice and Has Superior Efficacy and Pharmacology with Less Toxicity Compared to Gossypol (NSC19048)." Blood 108, no. 11 (2006): 2487. http://dx.doi.org/10.1182/blood.v108.11.2487.2487.

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Abstract Altered expression of Bcl-2-family proteins plays a central role in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity, pharmacology, and efficacy in mice of Gossypol (NSC19048) and ApoGossypol (NSC736630), a semi-synthetic analog of natural product Gossypol, in which two reactive aldehydes were eliminated from the compound (Becattini, et al Chem & Biol 11(3):389-95, 2004 Mar.). Gossypol and ApoGossypol mimic endogenous BH3 peptide-containing antagonists of anti-apoptotic B
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9

Zaidi, R., and S. M. Hadi. "Interaction of gossypol with DNA." Toxicology in Vitro 6, no. 1 (1992): 71–76. http://dx.doi.org/10.1016/0887-2333(92)90087-8.

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10

Heywood, R., G. K. Lloyd, S. K. Majeed, and C. Gopinath. "The toxicity of gossypol to the male rat." Toxicology 40, no. 3 (1986): 279–84. http://dx.doi.org/10.1016/0300-483x(86)90060-0.

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11

Akingbemi, B. T., P. V. V. Prasada Rao, and T. A. Aire. "Ethanol Intake may Modify Gossypol Toxicosis in the Rat." Journal of Applied Toxicology 16, no. 5 (1996): 375–80. http://dx.doi.org/10.1002/(sici)1099-1263(199609)16:5<375::aid-jat350>3.0.co;2-c.

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12

Manabe, Sunao, David C. Nuber, and Young C. Lin. "Zone-specific hepatotoxicity of gossypol in perfused rat liver." Toxicon 29, no. 6 (1991): 787–90. http://dx.doi.org/10.1016/0041-0101(91)90071-x.

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13

Fonseca, Nayanna Brunna da Silva, Ivana Cristina Nunes Gadelha, Sílvia Catarina Salgado Oloris, and Benito Soto-Blanco. "Effectiveness of albumin-conjugated gossypol as an immunogen to prevent gossypol-associated acute hepatotoxicity in rats." Food and Chemical Toxicology 56 (June 2013): 149–53. http://dx.doi.org/10.1016/j.fct.2013.02.010.

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14

Buser, Michael D., and Hamed K. Abbas. "MECHANICALLY PROCESSING COTTONSEED TO REDUCE GOSSYPOL AND AFLATOXIN LEVELS." Journal of Toxicology: Toxin Reviews 20, no. 3-4 (2001): 179–208. http://dx.doi.org/10.1081/txr-100108556.

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15

Messiha, F. S. "Behavioral and metabolic interaction between gossypol and ethanol." Toxicology Letters 57, no. 2 (1991): 175–81. http://dx.doi.org/10.1016/0378-4274(91)90144-u.

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16

El-Sharaky, A. S., M. M. Wahby, M. M. Bader El-Dein, R. A. Fawzy, and I. N. El-Shahawy. "Mutual anti-oxidative effect of gossypol acetic acid and gossypol–iron complex on hepatic lipid peroxidation in male rats." Food and Chemical Toxicology 47, no. 11 (2009): 2735–41. http://dx.doi.org/10.1016/j.fct.2009.08.001.

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17

Monsees, Thomas K., Udo Winterstein, Wolf-bernhard Schill, and Werner Miska. "Influence of gossypol on the secretory function of cultured rat sertoli cells." Toxicon 36, no. 5 (1998): 813–16. http://dx.doi.org/10.1016/s0041-0101(97)00162-1.

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18

Barhoumi, R. "Kinetic Analysis of the Chronology of Patulin- and Gossypol-Induced Cytotoxicityin Vitro." Fundamental and Applied Toxicology 30, no. 2 (1996): 290–97. http://dx.doi.org/10.1006/faat.1996.0067.

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19

BARHOUMI, ROLA, and ROBERT C. BURGHARDT. "Kinetic Analysis of the Chronology of Patulin- and Gossypol-Induced Cytotoxicity in Vitro." Toxicological Sciences 30, no. 2 (1996): 290–97. http://dx.doi.org/10.1093/toxsci/30.2.290.

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20

Thirukkumar, S., G. Hemalatha, S. Vellaikumar, M. Murugan, and S. Amutha. "Influence of enzymes and extraction conditions on high yield of cottonseed milk." Journal of Environmental Biology 42, no. 4(SI) (2021): 1195–200. http://dx.doi.org/10.22438/jeb/42/4(si)/mrn-1584a.

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Aim: This research aimed to optimize suitable hydrolytic enzymes for maximizing cottonseed milk extracts for high cottonseed milk yield, protein content and low gossypol level. Methodology: Known amount of cottonseed was soaked for 90 min at 32°C and blended (cottonseed:water@1:6). Different aliquots of the blended cottonseed slurry were treated with 1% of enzymes viz., protease, cellulase and α-amylase enzyme at pH 7.0 followed by incubation at 40 and 52°C for 2.30 hr for the extraction of cottonseed milk. The enzyme activity of extracted milk was subsequently inactivated by pasteurization (9
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21

Lin, Qiu-Ru, Chen-Guang Li, Qing-Bing Zha, et al. "Gossypol induces pyroptosis in mouse macrophages via a non-canonical inflammasome pathway." Toxicology and Applied Pharmacology 292 (February 2016): 56–64. http://dx.doi.org/10.1016/j.taap.2015.12.027.

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22

Quintana, Penelope J. E., Ann de Peyster, Stephen Klatzke, and Hyun Jung Park. "Gossypol-induced DNA breaks in rat lymphocytes are secondary to cytotoxicity." Toxicology Letters 117, no. 1-2 (2000): 85–94. http://dx.doi.org/10.1016/s0378-4274(00)00244-7.

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23

Buttar, H. S., and B. N. Nayak. "Cytogenetic effects of vaginally administered gossypol in murine bone marrow cells." Toxicology Letters 38, no. 3 (1987): 251–56. http://dx.doi.org/10.1016/0378-4274(87)90005-1.

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24

Hutchinson, Richard W., Rola Barhoumi, Jared M. Miles, and Robert C. Burghardt. "Attenuation of Gossypol Cytotoxicity by Cyclic AMP in a Rat Liver Cell Line." Toxicology and Applied Pharmacology 151, no. 2 (1998): 311–18. http://dx.doi.org/10.1006/taap.1998.8461.

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25

YE, YI-XIN, DAVID BOMBICK, KENDALYN HIRST, et al. "The Modulation of Gap Junctional Communication by Gossypol in Various Mammalian Cell Lines in vitro." Toxicological Sciences 14, no. 4 (1990): 817–32. http://dx.doi.org/10.1093/toxsci/14.4.817.

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26

Tone, J. N., and D. R. Jensen. "Radioiron Utilization and Gossypol Acetic Acid in Male Rats." Drug and Chemical Toxicology 8, no. 1-2 (1985): 69–82. http://dx.doi.org/10.3109/01480548509011635.

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27

Lin, Young C., Tim Dietrick, Yasuko Rikihisa, and Winston L. Beane. "Antifertility effect of gossypol in male Japanese quail." Life Sciences 42, no. 22 (1988): 2283–92. http://dx.doi.org/10.1016/0024-3205(88)90381-5.

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28

YE, Y. "The modulation of gap junctional communication by gossypol in various mammalian cell lines in vitro*1." Fundamental and Applied Toxicology 14, no. 4 (1990): 817–32. http://dx.doi.org/10.1016/0272-0590(90)90306-5.

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29

Hu, Jianan, Yun Huang, Minru Xiong, Shafei Luo, Yong Chen, and Yuanjian Li. "The Effects of Natural Flavonoids on Lipoxygenase-Mediated Oxidation of Compounds with a Benzene Ring Structure—A New Possible Mechanism of Flavonoid Anti-Chemical Carcinogenesis and Other Toxicities." International Journal of Toxicology 25, no. 4 (2006): 295–301. http://dx.doi.org/10.1080/10915810600746122.

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Numerous studies have strongly suggested that flavonoids exhibit antimutagenic, anticarcinogenic, antiallergic, and anti-inflammatory properties, but the mechanism is still far from clear. In this study, the effect of natural flavonoid compounds, such as green tea polyphenol, epigallocatechin gallate, quercetin, and rutin on lipoxygenase-mediated co-oxidation of guaiacol, benzidine, paraphenylenediamine, and dimethoxybenzidine was investigated. Green tea polyphenol, epigallocatechin gallate, quercetin, and rutin can reduce the co-oxidation reaction speed of tested compounds mediated by soybean
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30

Best, Robert G., and Wendell H. McKenzie. "Variable sister-chromatid exchange response in human lymphocytes exposed in vitro to gossypol acetic acid." Mutation Research/Genetic Toxicology 206, no. 2 (1988): 227–33. http://dx.doi.org/10.1016/0165-1218(88)90165-6.

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31

Jo, C., H. S. Yook, M. S. Lee, et al. "Irradiation effects on embryotoxicity and oxidative properties of gossypol dissolved in methanol." Food and Chemical Toxicology 41, no. 10 (2003): 1329–36. http://dx.doi.org/10.1016/s0278-6915(03)00125-x.

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32

Zaidi, Rana, and S. M. Hadi. "Strand scission in DNA by Gossypol and Cu(II): Role of Cu(I) and oxygen-free radicals." Journal of Biochemical Toxicology 7, no. 4 (1992): 213–17. http://dx.doi.org/10.1002/jbt.2570070404.

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33

Ding, Zhi-Ming, Yang-Wu Chen, Yong-Sheng Wang, et al. "Gossypol exposure induces mitochondrial dysfunction and oxidative stress during mouse oocyte in vitro maturation." Chemico-Biological Interactions 348 (October 2021): 109642. http://dx.doi.org/10.1016/j.cbi.2021.109642.

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34

Majumdar, Shyamal K., Eileen P. Daly, Katherine M. Kleemeyer, Curtis C. Daehler, Michelle A. Baker, and R. R. Tice. "Genotoxic effects of gossypol acetic acid on cultured murine erythroleukemia cells." Environmental and Molecular Mutagenesis 18, no. 3 (1991): 212–19. http://dx.doi.org/10.1002/em.2850180309.

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35

Benz, C. C., S. B. Iyer, H. S. Asgari, S. A. Matlin, F. R. Aronson, and A. Barchowsky. "Gossypol effects on endothelial cells and tumor blood flow." Life Sciences 49, no. 12 (1991): PL67—PL72. http://dx.doi.org/10.1016/0024-3205(91)90178-e.

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36

Chen, Yu, M. Sten, M. Nordenskjöld, B. Lambert, S. A. Matlin, and R. H. Zhou. "The effect of gossypol on the frequency of DNA-strand breaks in human leukocytes in vitro." Mutation Research/Environmental Mutagenesis and Related Subjects 164, no. 1 (1986): 71–78. http://dx.doi.org/10.1016/0165-1161(86)90043-9.

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37

Abou-Donia, Mohamed B., Mohamed A. Othman, and Patience Obih. "Interspecies comparison of pharmacokinetic profile and bioavailability of (±)-gossypol in male Fischer-344 rats and male B6C3F mice." Toxicology 55, no. 1-2 (1989): 37–51. http://dx.doi.org/10.1016/0300-483x(89)90173-x.

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38

Jia, Lee, Lori C. Coward, Corenna D. Kerstner-Wood, et al. "Comparison of pharmacokinetic and metabolic profiling among gossypol, apogossypol and apogossypol hexaacetate." Cancer Chemotherapy and Pharmacology 61, no. 1 (2007): 63–73. http://dx.doi.org/10.1007/s00280-007-0446-3.

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39

Liu, Hongming, Hua Sun, Danyi Lu, et al. "Identification of glucuronidation and biliary excretion as the main mechanisms for gossypol clearance:in vivoandin vitroevidence." Xenobiotica 44, no. 8 (2014): 696–707. http://dx.doi.org/10.3109/00498254.2014.891780.

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40

Zhou, De-Rong, Yong-Cui Zhou, Guang-Hui Cui, et al. "Gossypol repressed the gap junctional intercellular communication between Sertoli cells by decreasing the expression of Connexin43." Toxicology in Vitro 22, no. 7 (2008): 1719–25. http://dx.doi.org/10.1016/j.tiv.2008.07.012.

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41

Nayak, B. N., and H. S. Buttar. "Induction of sister chromatid exchanges and chromosome damage by gossypol in bone marrow cells of mice." Teratogenesis, Carcinogenesis, and Mutagenesis 6, no. 2 (1986): 83–91. http://dx.doi.org/10.1002/tcm.1770060202.

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42

Zhang, Wen-Ju, Zi-Rong Xu, Shun-Hong Zhao, Jun-Fang Jiang, Yan-bo Wang, and Xiang-Hua Yan. "Optimization of process parameters for reduction of gossypol levels in cottonseed meal by Candida tropicalis ZD-3 during solid substrate fermentation." Toxicon 48, no. 2 (2006): 221–26. http://dx.doi.org/10.1016/j.toxicon.2006.05.003.

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43

Lin, Y. C., Y. Gu, R. W. Brueggemeier, and Y. Rikihisa. "Binding of 3H-gossypol in organelles of cultured bovine luteal cells." Life Sciences 50, no. 6 (1992): 443–47. http://dx.doi.org/10.1016/0024-3205(92)90379-4.

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44

Haasler, Lisa, Arun Kumar Kondadi, Thanos Tsigaras, et al. "The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro." Archives of Toxicology 95, no. 4 (2021): 1349–65. http://dx.doi.org/10.1007/s00204-021-02987-4.

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AbstractA major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms. To prevent undesired side effects due to toxicity on normal (healthy) cells, concentrations only toxic for tumor cells have been elaborated. Viability assays were performed to determine the cytotoxicity of GP in A375 melanoma and normal (he
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45

Gawai, K. R., C. Cox, J. Jackson, and R. R. Dalvi. "Changes in the Activity of Metabolic and Non-Metabolic Liver Enzymes in Rats Following Co-Administration of Gossypol with Phenobarbital." Pharmacology & Toxicology 76, no. 4 (1995): 289–91. http://dx.doi.org/10.1111/j.1600-0773.1995.tb00145.x.

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46

Lin, Y. C., Y. F. Hu, C. J. G. Chang, P. P. Moh, and S. K. Kulp. "Transfer of 3H-gossypol to neonatal rats via milk of nursing dams." Life Sciences 51, no. 21 (1992): 1657–65. http://dx.doi.org/10.1016/0024-3205(92)90310-l.

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47

El-Sharaky, A. S., A. A. Newairy, N. M. Elguindy, and A. A. Elwafa. "Spermatotoxicity, biochemical changes and histological alteration induced by gossypol in testicular and hepatic tissues of male rats." Food and Chemical Toxicology 48, no. 12 (2010): 3354–61. http://dx.doi.org/10.1016/j.fct.2010.09.004.

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48

Uzunoglu, Selim, Burcak Karaca, Harika Atmaca, et al. "Comparison of XTT and Alamar blue assays in the assessment of the viability of various human cancer cell lines by AT-101 (−/− gossypol)." Toxicology Mechanisms and Methods 20, no. 8 (2010): 482–86. http://dx.doi.org/10.3109/15376516.2010.508080.

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49

Lin, Y. C., A. Sanbuissho, S. Coskun, and Y. Rikihisa. "Inhibition of in vitro fertilization and early embryonic development in hamsters by gossypol." Life Sciences 55, no. 14 (1994): 1139–45. http://dx.doi.org/10.1016/0024-3205(94)00242-8.

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50

Lin, Young C., Takao Fukaya, Yasuko Rikihisa, and Amelia Walton. "Gossypol in female fertility control: Ovum implantation and early pregnancy inhibited in rats." Life Sciences 37, no. 1 (1985): 39–47. http://dx.doi.org/10.1016/0024-3205(85)90623-x.

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