ENHANCEMENT OF HEPATOCARCINOGENESIS AND INDUCTION OF SPECIFIC CYTOCHROME P450-DEPENDENT MONOOXYGENASE ACTIVITIES BY THE BARBITURATES ALLOBARBITAL, APROBARBITAL, PENTOBARBITAL, SECOBARBITAL AND 5-PHENYLBARBITURIC AND 5-ETHYLBARBITURIC ACIDS

To test predictions that barbiturates which are long-acting sedatives and/or strong inducers of CYP2B-mediated monooxygenase activities woul d be effective promoters of hepatocarcinogenesis, a series of clinical ly-useful barbiturates and structural analogs were tested for ability to promote hepatocellular carcinogenesis in male F344/NCr rats initiat ed with N-nitrosodiethylamine and for efficacy as inducers of CYP2B ac tivity in non-initiated rats of the same sex and strain. The barbitura tes were administered in the diet at concentrations equimolar to 500 p .p.m. of the known liver tumor promoter phenobarbital, which served as the positive control for this study. Phenobarbital, which has the lon gest duration of sedative action of this series of compounds, caused t he greatest induction of CYP2B activity, and displayed strong liver tu mor promoting effects. Allobarbital and aprobarbital, two intermediate -duration sedatives, were found to promote hepatocarcinogenesis, with allobarbital proving to be as effective as phenobarbital in this respe ct and aprobarbital being somewhat weaker as a promoter. These interme diate-duration sedatives were each relatively weak CYP2B-type inducers , causing similar to 25% of the induction displayed by phenobarbital. The nonsedatives, 5-phenyl- and 5-ethylbarbituric acids, were essentia lly inactive as CYP2B-type inducers and were also found to be relative ly inactive as promoters of hepatocarcinogenesis. Of the shorter-durat ion sedatives, pentobarbital was found to promote, and was relatively effective as a CYP2B-type inducer, while secobarbital showed little or no promoting activity and was less effective as an inducer of CYP2B a ctivities. Pentobarbital thus proved an important exception to our hyp othesis that only long-acting sedative barbiturates would promote hepa tocarcinogenesis. Although both the durations of sedative action and t he degrees of CYP2B-type induction exhibited by these compounds correl ate with a quantitative parameter for liver tumor-promoting activity ( relative promotion index), neither parameter appears to be sufficient, by itself, as a predictor of promoting activity for rat liver.