Abstract
Species differences in the intrinsic clearance (CLint) and the enzymes involved in the metabolism of pyrethroid pesticides were examined in rat and human hepatic microsomes. The pyrethroids bifenthrin, S-bioallethrin, bioresmethrin, β-cyfluthrin, cypermethrin, cis-permethrin, and trans-permethrin were incubated in rat and human hepatic microsomes in the presence or absence of NADPH. Metabolism was measured using a parent depletion approach. The CLint of the pyrethroids was 5- to 15-fold greater in rat relative to human microsomes except for trans-permethrin, which was approximately 45% greater in human microsomes. The metabolism of bifenthrin, S-bioallethrin, and cis-permethrin in rat and human hepatic microsomes was solely the result of oxidative processes. The metabolism of bioresmethrin and cypermethrin in human hepatic microsomes was solely the result of hydrolytic processes. Bioresmethrin and cypermethrin in rat hepatic microsomes and β-cyfluthrin and trans-permethrin in microsomes from both species were metabolized by both oxidative and hydrolytic pathways. The metabolism of trans-permethrin was reduced when incubated with its diastereomer, cis-permethrin, in both rat and human hepatic microsomes. Rat cytochrome P450 (P450) isoforms that showed activity toward several pyrethroids included CYP1A1, CYP1A2, CYP2C6, CYP2C11, CYP3A1, and CYP3A2. Human P450 isoforms that showed activity toward multiple pyrethroids were CYP2C8, CYP2C9, CYP2C19, and CYP3A4. Species-specific differences in metabolism may result in variable detoxification of pyrethroids, which may in turn result in divergent neurotoxic outcomes. These species differences and isomer interactions in metabolism of pyrethroids should be considered when assessing the potential adverse health effects of pyrethroid pesticides.
Footnotes
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This work was supported in part by the National Health and Environmental Effects Research Laboratory–Department of Environmental Sciences and Engineering Environmental Protection Agency [Grant CT826513].
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This article has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.022343.
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ABBREVIATIONS: P450, cytochrome P450; CLint, intrinsic clearance; bifenthrin, (2-methyl[1,1′-biphenyl]-3-yl)methyl (1R,3R)-rel-3-[(1Z)-2-chloro-3,3,3-trifluoro-1-propenyl]-2,2-dimethylcyclopropanecarboxylate; S-bioallethrin, 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R,3R)-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate; bioresmethrin, [5-(phenylmethyl)-3-furanyl]methyl (1R,3R)-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate; β-cyfluthrin, cyano(4-fluoro-3-phenoxyphenyl)methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecaroboxylate; λ-cyhalothrin, (R)-cyano(3-phenoxyphenyl)methyl (1S,3S)-rel-3-[(1Z)-2-chloro-3,3,3-trifluro-1-propenyl]-2,2-dimethylcyclopropanecarboxylate; cypermethrin, cyano(3-phenoxyphenyl)methyl 3-(2,2-dichoroethenyl)-2,2-dimethylcyclopropanecarboxylate; cis-permethrin, (3-phenyoxybenzyl (1RS)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate); trans-permethrin, (3-phenyoxybenzyl (1RS)-trans-3-(2,2-dichloroethenyl)-2,2-dimethyl-cyclopropanecarboxylate); resmethrin, [5-(phenylmethyl)-3-furanyl]methyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate; permethrin, 3-phenoxyphenyl)methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate; LC, liquid chromatography.
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↵1 Current affiliation: United States Environmental Protection Agency, Office of Pesticides Program, Health Effects Division, Alexandria, Virginia.
- Received May 13, 2008.
- Accepted October 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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In Vitro Metabolism of Pyrethroid Pesticides by Rat and Human Hepatic Microsomes and Cytochrome P450 Isoforms
