Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene

Abstract

The effect of tetrachloroethylene on Phase I and II drug-metabolizing enzymes in rat liver was examined. Rats were treated orally with tetrachloroethylene daily for five days, at doses of 125, 250, 500, 1,000 and 2,000 mg/kg. The higher doses (> 500 mg/kg) of tetrachloroethylene induced the hepatic microsomal 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase activities associated with the CYP2B subfamily. 7-ethoxyresorufin O-deethylase activity was also induced about 2-fold compared with that of control rats at 500, 1,000, and 2,000 mg/kg dose levels of tetrachloroethylene. However, 7-ethoxycoumarin O-deethylase and 7-methoxyresorufin O-demethylase activities were increased significantly at only the 1,000 mg/kg dose level of tetrachloroethylene (1.4- and 1.5-fold). Although other cytochrome P450-mediated monooxygenase activities such as nitrosodimethylamine N-demethylase, aminopyrine N-demethylase and erythromycin N-demethylase were also induced by tetrachloroethylene, the relative induction to control activity was lower than those of 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase. Western immunoblotting showed that the levels of CYP2B1 and CYP2B2 proteins in liver microsomes were increased at doses of 1,000 and 2,000 mg/kg of tetrachloroethylene. In addition to cytochrome P450-mediated monooxygenases, there was significant induction of the Phase II drug-metabolizing enzymes, DT-diaphorase, glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and UDP-glucuronyltransferase activities towards 4-nitrophenol and 7-hydroxycoumarin. The results indicate that tetrachloroethylene induces both Phase I (CYP2B-mediated monooxygenase) and Phase II drug-metabolizing enzymes (DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase) in the rat liver.

Induction of glutathione S‐transferases activities in Drosophila melanogaster exposed to phenol

“…Several chemicals have been reported to induce Gsts activities in fruit flies, such as benzo(a)pyrene (Cervello et al, 1992), oxadiaolone (Hunaiti et al, 1995), pentobarbital (Tang and Tu, 1995), tetrachloroethylene (Hanioka et al, 1995), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (Schrenk et al, 1995). After long-term exposure of fruit flies to phenol, both cytosolic fractions and affinity column purified Gsts activities from phenol-treated fruit flies were all higher than those measured from wild type strain.…”

“…Induction of Gsts could increase the amount of Gst proteins and elevate total enzyme activities (Bhagwat et al, 1998). Many chemicals have been reported as capable of inducing insect Gsts activities such as phenobarbital (Hayaoka and Dauterman, 1983;Lubet et al, 1992), pentobarbital (Tang and Tu, 1995), benzo(a)pyrene (Cervello et al, 1992), tetrachloroethylene (Hanioka et al, 1995), 2,3,7,8-tetrachlorodibenzo-p-dioxin (Schrenk et al, 1995, and oxadiaolone (Hunaiti et al, 1995).…”

Effect of Trichloroethylene on Cytochrome P450 Enzymes in the Rat Liver

“…Also, it is suggested that tetrachloroethylene is metabolized by only phenobarbital-inducible P450 (Costa and Ivanetich 1980), whereas TCE is mainly metabolized by CYP2E1 or CYP2B1 /2 in the mouse and rat in vitro (Nakajima et al 1992). On the other hand, we reported that tetrachloroethylene markedly induces CYP2B1/2 in the rat liver (Hanioka et al 1995). This study indicated that TCE Figure 1.…”

Drug-Metabolizing Enzymes Mechanisms and Functions

“…It has been established that the activities of MFO are very low at birth but increase rapidly in adult and then subsequently decline in adult in all animal species including man [48][49][50][51][52]. For example, the cytochrome P450 1A mediated 2hydroxylation of biphenyl was present in neonatal rat and rabbit livers but this isozyme was not detected during adulthood [53,54].…”