Comparative metabolism of chloroacetamide herbicides and selected metabolites in human and rat liver microsomes.

Acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methyl-phenyl)-acetamide ], alachlor [N-(methoxymethyl)- 2-chloro-N-(2,6-diethyl-phenyl)acetamide], butachlor [N-(butoxymethyl)-2-chloro-N-(2,6-diethyl-phenyl)acetamide], and metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl ) acetamide] are pre-emergent herbicides used in the production of agricult ural crops. These herbicides are carcinogenic in rats: acetochlor and alach lor cause tumors in the nasal turbinates, butachlor causes stomach tumors, and metolachlor causes liver tumors. It has been suggested that the carcino genicity of these compounds involves a complex metabolic activation pathway leading to a DNA-reactive dialkylbenzoquinone imine. Important intermediat es in this pathway are 2-chloro-N-(2-methyl-6-diethylphenyl)acetamide (CDEP A) produced from alachlor and butachlor and 2-chloro-N-(2-methyl-6-ethylphe nyl)acetamide (CMEPA) produced from acetochlor and metolachlor. Subsequent metabolism of CDEPA and CMEPA produces 2,6-diethylaniline (DEA) and 2-methy l-6-ethylaniline (MEA), which are bioactivated through para-hydroxylation a nd subsequent oxidation to the proposed carcinogenic product dialkylbenzoqu inone imine. The current study extends our earlier studies with alachlor an d demonstrates that rat liver microsomes metabolize acetochlor and metolach lor to CMEPA (0.065 nmol/min/mg and 0.0133 nmol/min/mg, respectively), wher eas human liver microsomes can metabolize only acetochlor to CMEPA (0.023 n mol/min/mg). Butachlor is metabolized to CDEPA to a much greater extent by rat liver microsomes (0.045 nmol/min/mg) than by human liver microsomes (< 0.001 nmol/min/mg). We have determined that both rat and human livers metab olize both CMEPA to MEA (0.308 nmol/min/mg and 0.541 nmol/min/mg, respectiv ely) and CDEPA to DEA (0.350 nmol/min/mg and 0.841 nmol/min/mg, respectivel y). We have shown that both rat and human liver microsomes metabolize MEA ( 0.035 nmol/min/mg and 0.069 nmol/min/mg, respectively) and DEA (0.041 nmol/ min/mg and 0.040 nmol/min/mg, respectively). We have also shown that the cy tochrome P450 isoforms responsible for human metabolism of acetochlor, buta chlor, and metolachlor are CYP3A4 and CYP2B6.