- Full (HTML) - Full (PDF) - Related EHP Articles - PubMed:Related Articles - PubMed:Citation - Cited in PMC - Purchase This Issue

Scott Coleman,¹ Russell Linderman,² Ernest Hodgson,¹ and Randy L. Rose¹

¹Department of Toxicology; ²Department of Chemistry, North Carolina State University, Raleigh, North Carolina, USA

Abstract

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 agricultural crops. These herbicides are carcinogenic in rats: acetochlor and alachlor cause tumors in the nasal turbinates, butachlor causes stomach tumors, and metolachlor causes liver tumors. It has been suggested that the carcinogenicity of these compounds involves a complex metabolic activation pathway leading to a DNA-reactive dialkylbenzoquinone imine. Important intermediates in this pathway are 2-chloro-N-(2,6-diethylphenyl) acetamide (CDEPA) produced from alachlor and butachlor and 2-chloro-N-(2-methyl-6-ethylphenyl) acetamide (CMEPA) produced from acetochlor and metolachlor. Subsequent metabolism of CDEPA and CMEPA produces 2,6-diethylaniline (DEA) and 2-methyl-6-ethylaniline (MEA) , which are bioactivated through para-hydroxylation and subsequent oxidation to the proposed carcinogenic product dialkylbenzoquinone imine. The current study extends our earlier studies with alachlor and demonstrates that rat liver microsomes metabolize acetochlor and metolachlor to CMEPA (0.065 nmol/min/mg and 0.0133 nmol/min/mg, respectively) , whereas human liver microsomes can metabolize only acetochlor to CMEPA (0.023 nmol/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 metabolize both CMEPA to MEA (0.308 nmol/min/mg and 0.541 nmol/min/mg, respectively) and CDEPA to DEA (0.350 nmol/min/mg and 0.841 nmol/min/mg, respectively) . 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 cytochrome P450 isoforms responsible for human metabolism of acetochlor, butachlor, and metolachlor are CYP3A4 and CYP2B6. Key words: chloroacetamide herbicides, human cytochrome P450, in vitro metabolism. Environ Health Perspect 108:1151-1157 (2000) . [Online 7 November 2000]

http://ehpnet1.niehs.nih.gov/docs/2000/108p1151-1157coleman/ abstract.html

Address correspondence to R.L. Rose, Department of Toxicology, P.O. Box 7633, North Carolina State University, Raleigh, NC 27695 USA. Telephone: (919) 515-4378. Fax: (919) 515-7169. E-mail: randy_rose@ncsu.edu

This work was supported by the North Carolina Department of Agriculture Environmental Trust Fund and the National Institute of Environmental Health Sciences grant T32 ES07046.

Received 5 May 2000 ; accepted 1 August 2000.