In Vitro Metabolism of Pyrethroid Pesticides by Rat and Human Hepatic Microsomes and Cytochrome P450 Isoforms

Abstract

ABSTRACT:Species differences in the intrinsic clearance (CL int ) and the enzymes involved in the metabolism of pyrethroid pesticides were examined in rat and human hepatic microsomes. The pyrethroids bifenthrin, S-bioallethrin, bioresmethrin, ␤-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 CL int 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 ␤-cyfluthrin and trans-permethrin in microsomes from both species were metabolized by both oxidative and hydrolytic pathways. The metabolism of transpermethrin was reduced when incubated with its diastereomer, cispermethrin, 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.

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

“…CYP-mediated oxidative metabolism of OPs and PYRs is complex and involves several pathways, as different CYP isoforms can metabolize the same compound (e.g., chlorpyrifos) and different compounds (e.g., deltamethrin) to different degrees (Mutch and Williams 2006;Godin et al, 2007;Scollon et al, 2009). However, when the relative abundance of the different isoforms is taken into account, the predominant hepatic Cyp enzymes (Cyp1a2, Cyp2c50, and Cyp3a11) are all considerably reduced during the course of gestation, especially at GD14.…”

The Toxicity of Fenitrothion and Permethrin

“…In general, trans isomer is more rapidly metabolized than cis isomer, which is related to the lower susceptibility of cis isomer to enzymatic hydrolysis of the ester linkage (Soderlund and Casida, 1977;Zhang et al, 2008). Besides hydrolytic pathway by carboxylesterase, oxidative metabolic pathway of both cis-and trans-permethrin in rat and human hepatic microsomes was recently reported (Scollon et al, 2009). The toxicokinetics of permethrin (with a cis:trans ratio of 25:75) was investigated after single oral doses to rats (Anadon et al, 1991).…”

Metabolism of Pyrethroids by Mosquito Cytochrome P450 Enzymes: Impact on Vector Control

“…Nevertheless efficiency of CYP6AA3 and CYP6P7 in deltamethrin degradation is 5-to 10-fold less effective than human CYP2C8 and CYP2C19. It is noteworthy that more than one P450s residing within an organism can metabolize pyrethroids as described for human and mosquito, multiple rat P450s are also found capable of pyrethroid metabolisms (Scollon et al, 2009). When comparing to An.…”

“…These results suggest that differences in metabolic activities among P450 enzymes in insects could be attributed to structural differences resulting in selectivity and different enzymatic activities against insecticides. In human, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 have been reported abilities to metabolize both type I and II pyrethroids (Godin et al, 2007;Scollon et al, 2009). The preference for type I pyrethroid in CYP6AA3 is similar to human CYP2C9 and CYP2C19, while similar metabolic activity toward both types of pyrethroids found for CYP6P7 is similar to that of human CYP2C8 enzyme (Scollon et al, 2009).…”

“…In human, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 have been reported abilities to metabolize both type I and II pyrethroids (Godin et al, 2007;Scollon et al, 2009). The preference for type I pyrethroid in CYP6AA3 is similar to human CYP2C9 and CYP2C19, while similar metabolic activity toward both types of pyrethroids found for CYP6P7 is similar to that of human CYP2C8 enzyme (Scollon et al, 2009). Nevertheless efficiency of CYP6AA3 and CYP6P7 in deltamethrin degradation is 5-to 10-fold less effective than human CYP2C8 and CYP2C19.…”