In vitro metabolism of etoposide (VP-16-213) by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins |
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| Authors: | N Haim J Nemec J Roman B K Sinha |
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| Affiliation: | 1. School of Postgraduate Studies and Research, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia;2. Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia;3. Centre for Bioactive Molecules & Drug Delivery, Institute for Research, Development and Innovation, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia;4. Faculty of Medicine & Biomedical Sciences, MAHSA University, Jln SP 2, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia;1. Department of Basic Sciences, Adeleke University, P.M.B. 250, Ede, Osun, Nigeria;2. School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100811, China;3. Department of Biochemistry, Faculty of Science, Adeleke University, Osun, Nigeria;4. Department of Biochemistry, Faculty of Natural and Agricultural Science, Mafikeng Campus, North West University, Mmabatho 2735, South Africa |
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| Abstract: | We have studied the metabolism of VP-16-213 (etoposide, VP-16), an antitumor agent, by mouse liver microsomes to reactive intermediates and the subsequent covalent binding to microsomal proteins. This metabolism was shown to involve the O-demethylation of VP-16 and resulted in the formation of a 3',4'-dihydroxy derivative (DHVP-16) which was identified by both HPLC and mass spectrometry. The formation of DHVP-16 was cytochrome P-450-mediated as indicated by its dependence on NADPH, its increased production following treatment of mice with phenobarbital, and its marked inhibition by SKF-525A and piperonyl butoxide. Furthermore, DHVP-16 formation required oxygen. Microsomal incubation of VP-16 resulted in an irreversible binding of the drug to the proteins, which was also shown to be cytochrome P-450 dependent. The covalent binding of the VP-16 metabolite(s) was inhibited by DHVP-16 in a dose-dependent fashion, suggesting that the reactive intermediates that bound to proteins were derived from DHVP-16. Electron spin resonance studies indicated that the same semiquinone radical was formed during enzymatic (oxidation or reduction) metabolism of DHVP-16 and the o-quinone derivative of VP-16 (VP-16-Q). VP-16-Q and its semiquinone radical are suggested to be the bioalkylating species. |
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