In vitro metabolism of carbaryl by human cytochrome P450 and its inhibition by chlorpyrifos.
Carbaryl is a widely used anticholinesterase carbamate insecticide. Although previous studies have demonstrated that carbaryl can be metabolized by cytochrome P450 (CYP), the identification and characterization of CYP isoforms involved in metabolism have not been described either in humans or in experimental animals. The in vitro metabolic activities of human liver microsomes (HLM) and human cytochrome P450 (CYP) isoforms toward carbaryl were investigated in this study. The three major metabolites, i.e. 5-hydroxycarbaryl, 4-hydroxycarbaryl and carbaryl methylol, were identified after incubation of carbaryl with HLM or individual CYP isoforms and analysis by HPLC. Most of the 16 human CYP isoforms studied showed some metabolic activity toward carbaryl. CYP1A1 and 1A2 had the greatest ability to form 5-hydroxycarbaryl, while CYP3A4 and CYP1A1 were the most active in generation of 4-hydroxycarbaryl. The production of carbaryl methylol was primarily the result of metabolism by CYP2B6. Differential activities toward carbaryl were observed among five selected individual HLM samples with the largest difference occurring in the production of carbaryl methylol. Co-incubations of carbaryl and chlorpyrifos in HLM greatly inhibited carbaryl metabolism. The ability of HLM to metabolize carbaryl was also reduced by pre-incubation of HLM with chlorpyrifos. Chlorpyrifos inhibited the generation of carbaryl methylol, catalyzed predominately by CYP2B6, more than other pathways, correlating with an earlier observation that chlorpyrifos is metabolized to its oxon primarily by CYP2B6. Therefore, carbaryl metabolism in humans and its interaction with other chemicals is reflected by the concentration of CYP isoforms in HLM and their activities in the metabolic pathways for carbaryl. (Supported by NCDA Environmental Trust Fund)
Tang
Jun
J
Department of Environmental and Molecular Toxicology, North Carolina State University, Box 7633, Raleigh, NC 27695, USA.
Cao
Yan
Y
Rose
Randy L
RL
Hodgson
Ernest
E
D000328:Adult; D012721:Carbaryl / Q000378:metabolism*; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007306:Insecticides / Q000378:metabolism* / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver; D015394:Molecular Structure
D065607:Cytochrome P-450 Enzyme Inhibitors; D007306:Insecticides; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D004390:Chlorpyrifos; D012721:Carbaryl