ASSOCIATION BETWEEN RESPONSIVENESS TO PHENOBARBITAL INDUCTION OF CYP2B1/2 AND 3A1 IN RAT HEPATIC HYPERPLASTIC NODULES AND THEIR ZONAL ORIGIN

To explore further the mechanism underlying the alteration in expression of P450 enzymes in hepatic preneoplastic lesions, expression of CYP2B1/2 and 3A1 in individual hepatic hyperplastic nodules induced by an aflatoxin B-1 (AFB) administration protocol and the Solt-Farber resistance protocol in male F344 rats was examined via immunohistology. In nodules induced by the resistance protocol, expression of both CYP2B1/2 and 3A1 proteins was highly variable among different nodules, whereas these P450 proteins were expressed in all nodules induced by the AFB protocol. Nodules induced by the resistance protocol have been shown previously to arise from throughout the acinar lobule. In contrast to the resistance protocol, the AFB protocol causes extensive periportal necrosis, potentially resulting in a heavy selection pressure for clonal expansion of initiated cells arising from the centrilobular area. As phenobarbital-induced expression of both CYP2B1/2 and 3A1 in normal liver is heavily localized to the centrilobular zone, these observations suggest that the ability of preneoplastic nodules to respond to induction of these P450 proteins is determined primarily from the zonal origin of the precursor hepatocytes. Thus, the nodules from the resistance protocol that express little or no CYP2B1/2 and 3A1 may have been derived from the periportal hepatocytes, whereas all the nodules in the AFB group and some of the nodules from the resistance protocol which expressed these P450 proteins in response to phenobarbital induction may have been derived from centrilobular hepatocytes.