Inhibition of CYP 1A2-dependent MROD activity in rat liver microsomes: an explanation of the hepatic sequestration of a limited subset of halogenated aromatic hydrocarbons.

Abstract

Many classes of halogenated aromatic compounds (HACs) are highly lipophilic environmental contaminants that exert toxic effects via the Ah receptor signal transduction pathway and whose metabolism generally involves monooxygenase enzymes of the CYP 1A family. Despite their lipophilicity, a high proportion of the body burden of certain polychlorinated dibenzo-p-dioxins and coplanar polychlorinated biphenyls is sequestered in liver, a process believed to involve CYP 1A2. In this work we examined HAC-induced inhibition of the demethylation of 7-methoxyresorufin, a process that is selectively catalyzed by CYP 1A2. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 3,3',4,4'-tetrachlorobiphenyl (PCB 77) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) were found to be strong competitive inhibitors of methoxyresorufin-O-demethylase activity, consistent with the high ability of hepatic tissue to sequester these compounds selectively.