Coordinate induction of glutathione S-transferase alpha, mu, and pi expression in murine liver after a single administration of oltipraz

Abstract

The antischistosomal agent oltipraz displays a unique ability to inhibit chemically induced carcinogenesis in a variety of animal models. Its apparent lack of carcinogen specificity and low toxicity make it an attractive candidate for further development as a chemopreventive agent. The mechanism by which oltipraz affords cellular protection is thought to involve the modulation of phase II detoxication enzymes. The present study examines the regulation of each class of glutathione S-transferase (EC 2.5.1.18) in mice after a single oral administration of oltipraz. Glutathione S-transferase activity in the liver increased in a dose-dependent manner after drug exposure. Oltipraz administration (1 g/kg, by gavage) elevated glutathione S-transferase activity to a maximum (4.5-fold) on day 4 after treatment. Western blot analyses demonstrated the induction of all three classes of glutathione S-transferase (alpha, mu, and pi) by oltipraz. Our murine studies suggest that the chemopreventive activity of oltipraz may be due in part to its ability to elevate glutathione S-transferase-mu activity. Consistent with this possibility, associations between the glutathione S-transferase-mu-null phenotype and increased risk for lung, larynx, and bladder cancer have been recently demonstrated in humans. Coordinate elevations in enzymatic activity were preceded by significant elevations in glutathione S-transferase alpha, mu, and pi RNA on day 2 after treatment. Although nuclear run-on assays confirmed the transcriptional induction of all three classes, the maintenance of elevations in enzymatic activity after RNA levels returned to base-line suggests that additional mechanisms are required to regulate glutathione S-transferase expression. Preclinical findings are presented that characterize the response of each class of glutathione S-transferase to oltipraz exposure and support the use of these enzymes as intermediate markers of the chemopreventive activity of oltipraz.