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Groups of four adult male rats [ZUR:SIV-Z] were pretreated with corn oil (control; 2ml/kg/day i.p. for 3 days), trans-stilbene-oxide (SO; 200 mg/kg/day i.p. for 2 days), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 µg/kg i.p. once, 4 days before killing), phenobarbital (PB; 1 g/liter in the drinking water for 8 days), and dieldrin (20 mg/kg/day i.p. for 3 or 9 days). They received an injection of [G-3H]benzo(a)pyrene (BaP, 31 µg/kg, 7.4·109 dpm/kg;i.v.) 16 h before killing. In the liver of each rat, five enzymatic activities and the covalent binding of BaP to DNA have been determined. The microsomal aryl hydrocarbon monooxygenase activity (AHM) ranged from 75% of control (SO) to 356% (TCDD), the nuclear AHM from 63% (SO) to 333% (TCDD). Microsomal epoxide hydrolase activity (EH) was induced up to 238% (PB), nuclear EH ranged from 86% (TCDD) to 218% (PB). A different extent of induction was observed in the two compartments. Highest induction of glutathione S-epoxide transferase activity (GST) was found with PB (202%). The DNA binding of BaP was modulated within 79% (dieldrin, 9 days) and 238% of control (TCDD). An enzyme digest of control DNA was analysed by Sephadex LH-20 chromatography. Multiple linear regression analysis with all data expressed as % of control yielded the following equation: DNA Binding= 1.49· Microsomal AHM-1.07 · Nuclear AHM+0.33 · Microsomal EH-0.52 · Nuclear EH+0.11 · Cytoplasmic GST+58.2. From this analysis it is concluded that (1) AHM located in the endoplasmic reticulum is most important in the formation of DNA-binding metabolites, (2) EH in the same compartment is not determinative in this respect nor has it a protective effect, (3) both membrane-bound enzyme activities located in the nucleus may inactivate potential ultimate carcinogens, and (4) cytoplasmic GST probably cannot reduce DNA binding due to its subcellular localization.

journal of cancer research and clinical oncology

Effect of selected induction of microsomal and nuclear aryl hydrocarbon monooxygenase and epoxide hydrolase as well as cytoplasmic glutathione S-epoxide transferase on the covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo