Metabolism of four resmethrin isomers by liver microsomes

Microsomal esterases of mouse and rat liver readily cleave the trans- but not the cis-isomers of resmethrin (5-benzyl-3-furylmethyl chrysanthemate). The ester linkage also appears to undergo oxidative cleavage when esterase attack is minimal, i.e., with (+)-cis- and particularly (?)-cis-resmethrin in microsome-NADPH systems and with any of the isomers when NADPH is added to microsomes pretreated with TEPP. Metabolites retaining the ester linkage are detected in significant amounts only with (+)-cis-resmethrin in which case they are formed by oxidation at either the trans(E)- or cis(Z)-methyl group of the isobutenyl moiety with or without oxidation of the benzylfurylmethyl group. Metabolites of each acid moiety include chrysanthemic acid and up to six derivatives of this acid formed by oxidation at the trans(E)- or cis(Z)-methyl group yielding the corresponding alcohol, aldehyde, or acid, with chrysanthemate isomer and enzyme source variations in the preferred site of oxidation. The major identified metabolite of the alcohol moiety is either benzylfurylmethanol or the corresponding carboxylic acid depending on the enzyme system used. In the course of microsomal oxidation, a fragment from the alcohol but not the acid moiety of (+)-trans- and (+)-cis-resmethrin is strongly bound to microsomal components. These findings confirm in vivo studies on the isomeric variations in metabolism of the resmethrin components.