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First published on March 31, 2006; DOI: 10.1124/dmd.105.009134

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Received for publication December 30, 2005.
Revised March 22, 2006.
Accepted for publication March 24, 2006.

Stereoselective Metabolism of Endosulfan by Human Liver Microsomes and Human Cytochrome P450 Isoforms

Hwa-Kyung Lee 1, Joon-Kwan Moon 1, Chul-Hee Chang 1, Hoon Choi 1, Hee-Won Park 1, Byeoung-Soo Park 1, Hye-Suk Lee 2, Eul-Chul Hwang 3, Young-Deuk Lee 4, Kwang-Hyeon Liu 5, Jeong-Han Kim 1*

1 School of Agricultural Biotechnology, Seoul National University 2 College of Pharmacy, Wonkwang University 3 College of Natural Resources and Life Science, Dong-A University 4 Division of Life and Environmental Science, Daegu University 5 Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine

* Address correspondence to: E-mail: kjh2404{at}snu.ac.kr

Abstract

Endosulfan (6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,3,4-benzo(e)dioxathiepin-3-oxide) is a broad-spectrum chlorinated cyclodiene insecticide. This study was performed to elucidate the stereoselective metabolism of endosulfan in human liver microsomes and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of endosulfan. Human liver microsomal incubation of endosulfan in the presence of NADPH resulted in the formation of the toxic metabolite, endosulfan sulfate. The intrinsic clearances (Clint) of endosulfan sulfate from {beta}-endosulfan were 3.4-fold higher than those from {alpha}-endosulfan, suggesting that {beta}-endosulfan would be cleared more rapidly than {alpha}-endosulfan. Correlation analysis between the known P450 enzyme activities and the rate of the formation of endosulfan sulfate in the 14 human liver microsomes showed that {alpha}-endosulfan metabolism is significantly correlated with CYP2B6-mediated bupropion hydroxylation and CYP3A-mediated midazolam hydroxylation, and that {beta}-endosulfan metabolism is correlated with CYP3A activity. The P450 isoform selective inhibition study in human liver microsomes and the incubation study of cDNA-expressed enzymes also demonstrated that the stereoselective sulfonation of {alpha}-endosulfan is mediated by CYP2B6, CYP3A4 and CYP3A5, and that that of {beta}-endosulfan is transformed by CYP3A4 and CYP3A5. The total Clint values of endosulfan sulfate formation catalyzed by CYP3A4 and CYP3A5 were consistently higher for {beta}-endosulfan than for the {alpha}-form (Clint of 0.67 versus 10.46 µl/min/nmol of P450, respectively). CYP2B6 enantioselectively metabolizes {alpha}-endosulfan, but not {beta}-endosulfan. These findings suggest that the CYP2B6 and CYP3A enzymes are major enzymes contributing to the stereoselective disposition of endosulfan.


Key words: CYP inhibition, cytochrome P450, cytochrome P450 isoforms, enzyme kinetics, human CYP enzymes, insecticides, kinetics, liver microsomes, metabolite kinetics


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