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In vitro metabolic clearance of pyrethroid pesticides by rat and human hepatic microsomes and cytochrome P450 isoforms
Citation:
SCOLLON, E., J. M. STARR, S. GODIN, M. J. DEVITO, AND M. F. HUGHES. In vitro metabolic clearance of pyrethroid pesticides by rat and human hepatic microsomes and cytochrome P450 isoforms. DRUG METABOLISM AND DISPOSITION. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 37(1):221-228, (2009).
Impact/Purpose:
This study examined the in vitro metabolism of several pyrethroid pesticides using rat and human hepatic microsomes and cytochrome P450 isoforms. Quantitating the disappearance of pyrethroids from the incubation mixture over time is a measure of their metabolism. With this information, the intrinsic clearance can be determined. Strucutrally, pyrethroids may have 1-3 chiral centers and thusly 2-8 enantiomers. These enantiomers, or at a higher level, diastereomers (cis and trans) may interact such that the metabolism of one isomer is affected. This could affect the toxicity of the pyrethroid “mixture”. The results showed that the pyrethroids examined are metabolized by either oxidative or hydrolytic or by both pathways. For example, metabolism of bifenthrin, S-bioallethrin and cis-permethrin in rat and human microsomes was solely oxidative. The elimination of bioresmethrin and cypermethrin in human microsomes was solely hydrolytic. Thus there are species differences in the in vitro metabolism of some pyrethroids. The metabolism of trans-permethrin was reduced when incubated with its diastereomer, cis-permethrin, in both rat and human hepatic microsomes. The metabolism of cis-permethrin was unaffected by trans-peremthrin. Specific rat and P450 isoforms showed activity towards several pyrethroids. For rat P450s tested, the most active were CYP2C6, 2C11, and 3A1. For human P450s tested, the most active was 2C19
Description:
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