Inhibition, activation, destruction, and induction of drug-metabolizing enzymes by trichloroethylene

Abstract

The effects of trichloroethylene on hepatic drug-metabolizing enzymes were investigated in the rat. In vitro, addition of trichloroethylene to the incubation mixture decreased the metabolism of ethylmorphine and that of hexobarbital by hepatic microsomes; the inhibition of hexobarbital metabolism was competitive; however, trichloroethylene enhanced p-nitrophenol glucuronyl transferase activity. In vivo, trichloroethylene (1 ml/kg, ip) inhibited the the metabolism of hexobarbital; microsomal cytochrome P-450 and total protoheme were unchanged in nonpretreated rats but were decreased in phenobarbital-pretreated rats. Repeated administration of trichloroethylene decreased microsomal cytochrome P-450 but increased the liver weight/body weight ratio, microsomal proteins, NADPH-cytochrome c reductase activity, aniline hydroxylase activity, the in vitro covalent binding of the chemically reactive metabolite of trichloroethylene to microsomal proteins, and p-nitrophenol glucuronyl transferase activity. It is concluded that trichloroethylene may activate glucuronyl transferase in vitro and inhibit, destroy, and induce enzymes of the microsomal mixed function oxidase system (MFOS) in vivo; on acute administration, it competitively inhibits drug metabolism by MFOS; on repeated administration, it simultaneously destroys cytochrome P-450 and induces microsomal enzymes.