The metabolism of R-20458 [(E)-6,7-epoxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene] in rat hepatocyte suspensions

Abstract

The metabolism of R-20458 [( E)-6,7-epoxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene] by rat hepatocytes has been analyzed and compared with that of juvenile hormone I [methyl-( E,E)-cis-10,11-epoxy-7-ethyl-3,11-dimethyl-2,6-tridecadienoate] under identical conditions. The metabolism of R-20458 is characterized by the predominance of NADPH-dependent cytochrome P-450 and epoxide hydrolase reactions; whereas, JH I is metabolized mainly by carboxylesterase, epoxide hydrolase, and glutathione S-transferases. The metabolites of R-20458 have been shown to correspond to ( E)-6,7-epoxy-1-(4-hydroxyethylphenoxy)-3,7-dimethyl-2-octene; ( E)-6,7-epoxy-1-(4-acetylphenoxy)-3,7-dimethyl-2-octene; ( E)-6,7-dihydroxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene; and, ( E)-6,7-dihydroxy-1-(4-acetylphenoxy)-3,7-dimethyl-2-octene. The production of the α-hydroxyethyl, p-acetylphenoxy, and acetylphenoxy-6,7-diol metabolites is markedly inhibited by SKF 525-A. No dramatic effects are produced by diethylmaleate and 1,2-epoxy-3,3,3-trichloropropane.