Abstract
To study the response of human glutathione S-transferase (GST) to chemical inducers, we have developed a line of transgenic rats which harbor 4.5 kb of human GST alpha I promoter region in their genome. This promoter is linked to the chloramphenicol acetyltransferase (CAT) reporter gene which allows determination of the expression of human GST in rat tissues. Three chemical inducers, which show clearly different induction profiles, phenobarbital (PB), β-naphthoflavone (BNF), and butylated hydroxyanisole (BHA), were administered to the transgenic rats. Induction of constitutive rat liver enzymes by the inducers, which was evaluated in terms of the activities of P450, GST, and UDP-glucuronosyltransferase in the liver tissues, were in agreement with what has been reported for non-transgenic rats. Expression of CAT protein was detected in the liver of the transgenic rats, and an unequivocal increase in CAT protein was found in the transgenic rats treated with PB. No remarkable changes in CAT protein were observed in the transgenic rats treated with BNF or BHA. Moreover, immunohistochemical staining with anti-CAT antibody revealed that the expression and increase of CAT protein were localized in the central zone of the liver lobule. The results of this study suggest that human GST alpha 1 is induced by PB, in particular, in the central zone of the liver lobule. The transgenic rat is concluded to be a useful animal model for predicting metabolizing functions in humans.
