PEROXISOME PROLIFERATORS INCREASE THE FORMATION OF BPDE-DNA ADDUCTS IN ISOLATED RAT HEPATOCYTES

Peroxisome proliferators are known to modulate the activity of xenobio tic-metabolising enzymes, including glutathione S-transferase (GST) an d cytochrome P-450 (CYP). In this study the effect of peroxisome proli ferators silver and di(2-ethylhexyl)phthalate (DEHP) on the formation )-anti-benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts from a proximate mutagen and carcinogen (-)-transbenzo(a)pyrene-7,8-di hydrodiol (BPDD) has been investigated. Rat CYP1A1 metabolises BPDD to mutagenic BPDE, which may form DNA adducts or, alternatively, be deto xified by hydrolysis or glutathione conjugation. In this experiment th e formation of BPDE-DNA adducts was significantly increased in hepatoc ytes isolated from all silver treated rats and two out of four DEHP tr eated rats (14 day treatment). The activity of CYP1A1 was increased wh ereas GST was reduced by the peroxisome proliferator silver. These cha nges were more significant than those induced by DEHP. We have hypothe sised that the formation of BPDE-DNA adducts was primarily due to the increased BPDD activation to BPDE versus reduced detoxication of BPDE. Other hepatic changes induced by the peroxisome proliferators, e.g. p eroxisome proliferation per se and increased mitotic activity of the l iver could have an effect on the outcome of BPDD exposure. (C) 1997 El sevier Science Ireland Ltd.