EFFECT OF 3-METHYLCHOLANTHRENE ADMINISTRATION ON EXPRESSION OF CYTOCHROME-P-450 ISOFORMS INDUCED BY PHENOBARBITAL IN RAT HEPATOCYTES

The effects of an inducer on expression of cytochrome P-450 (P-450) is oforms induced antecedently by another inducer are unknown. Thus, we e xamined the amount of phenobarbital (PB)-inducible P-450 isoforms (P-4 50 2B1/2B2) in hepatocytes from rats injected first with PB and then w ith 3-methylcholanthrene (MC) (PB + MC-treated animals) by quantitativ e immunohistochemistry. In addition, expression of P-450 2B2 mRNA was examined by in situ hybridization. In PB-treated animals, P-450 2B1/2B 2 content increased in perivenular and midzonal hepatocytes. In PB+MC- treated animals, however, the PB-induced increase in 2B1/2B2 content w as suppressed in perivenular hepatocytes but promoted in midzonal hepa tocytes. The hybridization signal for P-450 2B2 mRNA appeared almost e xclusively in perivenular hepatocytes after 24 hr of PB injection and disappeared after 48 hr of injection. In PB+MC-treated animals, howeve r, strong hybridization signal was observed in midzonal and perivenula r hepatocytes after 48 hr of PB injection. The promotion of the increa se in P-450 2B1/2B2 content in midzonal hepatocytes in PB+MC-treated a nimals probably corresponds to the strong hybridization signal, wherea s there appeared to be a divergence between the intensity of the signa l and the content in perivenular hepatocytes, The results indicate tha t MC administration drastically influences the pattern of expression o f P-450 isoforms induced by PB in perivenular and midzonal hepatocytes .