DOSE-DEPENDENT ACINAR INDUCTION OF CYTOCHROMES-P450 IN RAT-LIVER - EVIDENCE FOR A DIFFERENTIAL MECHANISM OF INDUCTION OF P450IA1 BY BETA-NAPHTHOFLAVONE AND DIOXIN

Rats received various doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Aroclor 1254 (ARO), beta-naphthoflavone (BNF) or phenobarbital (PB), and the hepatic expression of cytochromes P450IA1 and/or P450IIB1/IIB2 was analysed by immunohistochemistry and Western blotting. A clear heterogeneous acinar induction of IA1 was detected when a low dose of TCDD, ARO or BNF was administered. When a low dose of TCDD or ARO was administered, IA1 was found to be induced primarily in hepatocytes located in acinus zone 3, whereas when a low dose of BNF was administered, IA1 was found to be preferentially induced in hepatocytes located in acinus zone 1. A clear zonal induction of IIB1/IIB2 was also observed when a low dose of PB or ARO was administered. Both compounds induced IIB1/IIB2 preferentially in hepatocytes located in acinus zone 3. When rats were administered high doses of TCDD, ARO, BNF or PB there was no zonal pattern of induction of IA1 or IIB1/IIB2; instead, a pan-acinar induction of these enzymes was observed. These results indicate that the overall hepatic concentration of IA1 or IIB1/IIB2 is merely dependent on the proportion of 'induced hepatocytes' within the acinus, which in turn depends on the dose of the inducer.