Metabolism of the arylamide herbicide propanil. I. Microsomal metabolism and in vitro methemoglobinemia

Abstract

Methemoglobinemia produced by exposure to the herbicide propanil (3,4-dichloropropionanilide) is thought to be mediated by toxic metabolites formed during the hepatic clearance of the parent compound. We examined the metabolism of propanil and 3,4-dichloroaniline in rat liver microsomes to identify metabolites that may be involved in propanil-induced methemoglobinemia. The major pathway of propanil metabolism in microsomal incubations was acylamidase-catalyzed hydrolysis to 3,4-dichloroaniline. The reaction did not require NADPH, and was inhibited by the acylamidase inhibitors paraoxon and sodium fluoride. Oxidized metabolites were isolated by high-performance liquid chromatography, and identified as 2'-hydroxypropanil and 6-hydroxypropanil by comparison of their mass and nuclear magnetic resonance spectra to those of synthetic standards. Major microsomal metabolites of 3,4-dichloroaniline were 6-hydroxy-3,4-dichloroaniline and N-hydroxy-3,4-dichloroaniline. Both N-hydroxy-3,4-dichloroaniline and 6-hydroxy-3,4-dichloroaniline directly oxidized hemoglobin in rat erythrocyte suspensions in a concentration-dependent manner; however, the potency of N-hydroxy-3,4-dichloroaniline was at least an order of magnitude greater than that of 6-hydroxy-3,4-dichloroaniline.