In vitro metabolism of alachlor by human liver microsomes and human cytochrome P450 isoforms

Alachlor (2-chloro-N-methoxymethyl-N-(2,6-diethylphenyl)acetamide) is a wid ely used pre-emergent chloroacetanilide herbicide which has been classified by the USEPA as a probable human carcinogen. The putative carcinogenic met abolite, 2, 6-diethylbenzoquinone imine (DEBQI), is formed through a comple x series of oxidative and non-oxidative steps which have been characterized in rats, mice, and monkeys but not in humans. A key metabolite leading to the formation of DEBQI is 2-chloro-N-(2, 6-diethylphenyl) acetamide (CDEPA) . This study demonstrates that male human liver microsomes are able to meta bolize alachlor to CDEPA. The rate of CDEPA formation for human liver micro somes (0.0031 +/- 0.0007 nmol/min per mg) is significantly less than the ra tes of CDEPA formation for rat liver microsomes (0.0353 +/- 0.0036 nmol/min per mg) or mouse liver microsomes (0.0106 +/- 0.0007). Further, we have sc reened human cytochrome P450 isoforms 1A1, 1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4 and determined that human CYP 3A4 is responsible for meta bolism of alachlor to CDEPA. Further work is necessary to determine the ext ent to which humans are able to metabolize CDEPA through subsequent metabol ic steps leading to the formation of DEBQI. (C) 1999 Elsevier Science Irela nd Ltd. All rights reserved.