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Regulation and expression of four cytochromes P-450 isoenzymes, NADPH-cytochrome P-450 reductase, the glutathione transferases B and C and microsomal epoxide hydrolase in preneoplastic and neoplastic lesions in rat liver
A. Buchmann, Wolf D. Kuhlmann, M. Schwarz, W. Kunz,
C. R. Wolf, E. Moll, T. Friedberg, F Oesch
Institute of Biochemistry, German Cancer Research Centre, D-6900 Heidelberg, FRG
Imperial Cancer Research Fund, Medical Oncology Unit, Edinburgh, UK
Institute of Toxicology, University of Mainz, D-6500 Mainz, FRG
Nitrosamine-induced hepatocarcinogenesis has been used to investigate the regulation and expression of different drug-metabolizing enzymes in preneoplastic and neoplastic lesions in the female Wistar rat. The enzymes investigated were two phenobarbital-inducible cytochrome P-450 (cyt. P-450) isoenzymes (PB1 and PB2, mol. wt. 52000 and 53500, respective-ly), two 3-methylcholanthrene-inducible forms (MC1 and MC2, mol. wt. 54500 and 57000, respectively), NADPH-cytochrome P-450 reductase, the cytosolic glutathione transferases (GSTs) B and C and the microsomal epoxide hydrolase with broad substrate specificity (mEHb).
Carcinogen-induced lesions were identified by use of the known markers of hepatocarcinogenesis adenosintriphosphatase and ã-glutamyl transpeptidase. While the GSTs and mEHb were increased in all preneoplastic and neoplastic lesions, the levels of the individual cyt. P-450 isoenzymes were characteristically different from each other. In many of the early ATPase deficient islets PB1 was elevated, whereas the content of the other cyt P-450 forms and NADPH-cytochrome P-450 reductase was either unchanged or slightly lowered. At later stages of hepatocarcinogenesis PB1 returned to the levels of the surrounding tissue, while the other cyt. P-450 isoenzymes were decreased, the most prominent reduction being found in MC1. In neoplastic nodules all cyt. P-450s and NADPH-cyt. P-450 reductase were diminuished, some of them dramatically.
These findings indicate that in spite of a common response of groups of P-450s to inducing agents, individual P-450 isoenzymes are also regulated separately. Moreover, the constant elevation of mEHb and GSTs in all lesions investigated in this study demonstrates that these enzymes, which are largely involved in deactiviation, are regulated in a different fashion from the predominantly carcinogen-activating monooxygenases. The observed differences in en-zyme pattern may provide a useful method for subdividing and categorizing preneoplastic and neoplastic lesions.