Comparison of the biological effects of phenobarbital and nafenopin on rat hepatocarcinogenesis.

In order to further analyze the biological effects of phenobarbital (PB) and nafenopin (NAF) on rat hepatocarcinogenesis, four experiments were undertaken. In the first one, their "promoting" effect on an ongoing carcinogenic process was analyzed. Rats were initiated by diethylnitrosamine treatment (I) and submitted two weeks later to a selection procedure (S). One week after 2-acetylaminofluorene (2-AAF) release, the animals received for up to 56 weeks a basal diet or a diet containing 0.05% of PB or 0.1% of NAF. The quantitative analysis of the gamma-glutamyl-transferase-positive lesions showed that, 8 to 19 weeks after I, PB enhanced the development of preneoplastic lesions whereas NAF inhibited it as compared to a group receiving a basal diet. However, both compounds enhanced the incidence and the yield of liver cancer starting 27 weeks after I (67% and 95%, respectively, vs 10%). In the second experiment, the effect of chronic administration of PB and NAF given after I without S or after S without I was analyzed. Within a period of observation of 27 to 32 weeks, the incidence of cancer was 10% after I/PB and 75% after I/NAF. No cancer developed after S/PB, S/NAF or NAF alone. The third experiment was designed to test whether NAF had an initiating or selecting effect. The results of the quantitative analysis of the gamma-glutamyl-transferase-positive lesions showed that as compared to diethylnitrosamine, NAF had no initiating effect. When NAF replaced 2-AAF in the selection procedure, few gamma-glutamyl-transferase-positive lesions and no cancer were detected 8 and 32 weeks after I. The fourth experiment indicated that NAF could not prevent the remodeling of preneoplastic lesions induced in the I/S protocol. Even though they both have a "promoting" effect in liver carcinogenesis as evidenced by the increased incidence and yield of cancer, PB and NAF act differently.