In vitro metabolism of carbofuran by human, mouse, and rat liver microsomes, and human cytochrome P450 isoforms.
Usmani KA; Hodgson E; Rose RL
Toxicologist 2004 Mar; 78(S-1):299
Carbofuran is a widely used carbamate pesticide in agricultural practice throughout the world. Its effect as a pesticide is due to its ability to inhibit acetylcholinesterase activity. The present study was designed to investigate the in vitro metabolism of carbofuran by pooled human liver microsomes (HLM), rat liver microsomes (RLM), mouse liver microsomes (MLM), and human cytochrome P450 (CYP) isoforms. Carbofuran is metabolized by CYPs leading to the production of a major ring oxidation metabolite, 3-hydroxycarbofuran, and two minor metabolites. Pooled HLM have a significantly higher Km value (1950 uM) than RLM Km (210 uM) and MLM Km (550 uM) for metabolism of carbofuran to its major metabolite, 3-hydroxycarbofuran. Intrinsic clearance rate calculations indicate that HLM metabolize carbofuran to 3-hydroxycarbofuran almost 14-fold lower than RLM and MLM. Among 16 human cDNA-expressed CYP enzymes examined, CYP3A4 and 2C19 were the major isoforms responsible for carbofuran metabolism to 3-hydroxycarbofuran. Use of phenotyped HLM demonstrated that individuals with high levels of CYP3A4 and 2C19 have the greatest potential to metabolize carbofuran to its major metabolite. The variation in carbofuran metabolism among 17 single-donor HLM samples is over 5-fold and the best correlation between CYP isoform activity and carbofuran metabolism was observed with CYP3A4.
In-vitro-studies; Laboratory-animals; Animals; Animal-studies; Agricultural-industry; Agricultural-chemicals; Pesticides; Pesticides-and-agricultural-chemicals; Humans; Liver
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
East Carolina University