Enantioselective Metabolism of the Endocrine Disruptor Pesticide Methoxychlor by Human Cytochromes P450 (P450s): Major Differences in Selective Enantiomer Formation by Various P450 Isoforms
Methoxychlor, a currently used pesticide that in mammals elicits proestrogenic/estrogenic activity and reproductive toxicity, has been classified as a prototype endocrine disruptor. Methoxychlor is prochiral, and its metabolites 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane (mono-OH-...
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Published in | Drug metabolism and disposition Vol. 30; no. 12; pp. 1329 - 1336 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.12.2002
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Subjects | |
Online Access | Get full text |
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Summary: | Methoxychlor, a currently used pesticide that in mammals elicits proestrogenic/estrogenic activity and reproductive toxicity,
has been classified as a prototype endocrine disruptor. Methoxychlor is prochiral, and its metabolites 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane
(mono-OH-M); 1,1,1-trichloro- 2-(4-methoxyphenyl)-2-(3, 4-dihydroxyphenyl)ethane (catechol-M); and 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(3,
4-dihydroxyphenyl)ethane (tris-OH-M) are chiral; whereas 1,1,1-trichloro-2, 2-bis(4-hydroxyphenyl)ethane (bis-OH-M) is achiral.
These metabolites are formed during methoxychlor incubation with liver microsomes or recombinant cytochrome P450s (rP450s).
Since methoxychlor-metabolite enantiomers may have different estrogenic/antiestrogenic/antiandrogenic activities than corresponding
racemates, the possibility that P450s preferentially generate or use R or S enantiomers, was examined. Indeed, rCYP1A2 and r2A6 mono-demethylated methoxychlor primarily into ( R )-mono-OH-M at 91 and 75%, respectively, whereas rCYP1A1, 2B6, 2C8, 2C9, 2C19, and 2D6 formed the ( S )-enantiomer at 69, 66, 75, 95, 96, and 80%, respectively. However, rCYP3A4, 3A5, and 2B1(rat) weakly demethylated methoxychlor
without enantioselectivity. Human liver microsomes generated ( S )-mono-OH-M (77â87%), suggesting that CYP1A2 and 2A6 display only minor catalytic contribution. P450 inhibitors demonstrated
that CYP2C9 and possibly 2C19 are major hepatic catalysts forming ( S )-mono-OH-M, and CYP1A2 is primarily involved in forming the ( R )-mono-OH-M. Demethylation rate of ( S )-mono-OH-M versus ( R )-mono-OH-M forming achiral bis-OH-M by rCYP1A2 was 97/3, compared with 15/85 and 17/83 for rCYP2C9 and 2C19, respectively,
indicating opposite substrate enantioselectivity of rCYP1A2 versus 2C9 and 2C19. Also, rCYP1A2 preferentially O -demethylated ( R )-catechol-M into ( R )-tris-OH-M (at 80%), contrasting r2C9 and r2C19 that yielded ( S )-tris-OH-M at 80 and 77%, respectively. Ortho -hydroxylation of mono-OH-M into catechol-M and bis-OH-M into tris-OH-M was primarily by 3A4 and was not enantioselective.
In conclusion, enantiomeric abundance of methoxychlor metabolites depends on the relative catalytic activity of the hepatic
P450 isoforms. |
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ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.30.12.1329 |