title: CYP3A5 mediates bioactivation and cytotoxicity of tetrandrine.
abstract: Tetrandrine is a diaryl ether-type bisbenzylisoquinoline alkaloid and has shown multiple pharmacological activities. Our early work demonstrated that tetrandrine produced acute pulmonary toxicity and that tetrandrine was biotransformed to a quinone methide-derived metabolite mediated by CYP3A enzymes. The formation of the reactive intermediate is suggested to be responsible for the pulmonary toxicity induced by tetrandrine. In the present study, a WI-38-based Cyp3a5 transgenic cell line (WI-38/Cyp3a5) was established to investigate the role of CYP3A5 in tetrandrine-induced cytotoxicity. The transgenic cells were found to be more susceptible to the cytotoxicity of tetrandrine than the wild-type cells (WI-38/Vector). WI-38/Cyp3a5 cells showed higher cellular ROS levels, higher LDH activities in culture media, but lower cellular GSH contents than those observed in WI-38/Vector cells after exposure to tetrandrine. And severer apoptosis were observed in WI-38/Cyp3a5 cells after treatment with tetrandrine: WI-38/Cyp3a5 cells had higher proportion of early and late apoptotic cells, higher expression levels of caspase-3, but lower level of Bcl-2 than WI-38/Vector cells. This study provided strong evidence that CYP3A5 participated in tetrandrine-induced cytotoxicity.
authors: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.|Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
authors: Ye
authors: Y
authors: Tian
authors: Division of Gastroenterology and Hepatology, Department of Pediatrics, Center for Developmental Therapeutics, Seattle Children's Research Institute, University of Washington, 1900 9th Ave, Seattle, WA, 98101, USA.
authors: Shuijie
authors: S
authors: Shen
authors: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.
authors: Yan
authors: Y
authors: Jiang
authors: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.
authors: Qi
authors: Q
authors: Shen
authors: Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China. zengsu@zju.edu.cn.
authors: Su
authors: S
authors: Zeng
authors: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. jiang.zheng@seattlechildrens.org.|Division of Gastroenterology and Hepatology, Department of Pediatrics, Center for Developmental Therapeutics, Seattle Children's Research Institute, University of Washington, 1900 9th Ave, Seattle, WA, 98101, USA. jiang.zheng@seattlechildrens.org.
authors: Jiang
authors: J
authors: Zheng
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000378:metabolism / Q000633:toxicity*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010957:Plasmids; D017382:Reactive Oxygen Species / Q000378:metabolism; D019076:Transgenes
chemical_list: D044182:Benzylisoquinolines; D017382:Reactive Oxygen Species; C009438:tetrandrine; D007770:L-Lactate Dehydrogenase; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione
keywords: Bioactivation; CYP3A5; Quinone methide; Tetrandrine