Carbon tetrachloride and 2-isopropyl-4-pentenamide-induced inactivation of cytochrome P-450 leads to heme-derived protein adducts |
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| Authors: | H W Davies S G Britt L R Pohl |
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| Affiliation: | 1. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China;2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China;3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;4. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China;5. Shanghai Whittlong Pharmaceutical Institute Co., Ltd, Shanghai, China;6. Xenofinder Co., Ltd, Suzhou, China;7. National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, China;1. Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan;2. Faculty of Pharmaceutical Science, Hiroshima International University, Hiroshma, Japan;3. Nihon Pharmaceutical University, Saitama, Japan |
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| Abstract: | When CCl4 was incubated with rat liver microsomes from phenobarbital-treated rats in an aerobic or anaerobic atmosphere, over 69% of the heme moiety of cytochrome P-450 was destroyed. At least 45% of the degraded heme under both reaction conditions was accounted for as heme-derived products irreversibly bound to microsomal proteins. Furthermore, 33% of the irreversibly bound products were bound specifically to a 54-kDa form of cytochrome P-450. A structurally different compound, 2-isopropyl-4-pentenamide, also destroyed the heme moiety of cytochrome P-450 and produced heme-derived adducts of microsomal proteins that accounted for 28% of the destroyed heme. These results represent a novel mechanism for the destruction of cytochromes P-450 by xenobiotics. |
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