SHORT COMMUNICATION: Phenobarbital selectively promotes initiated cells with reduced TGFβ receptor levels

Phenobarbital (PB) is a potent tumor promoter in rodentliver. In this study we investigated whether PB selectivelypromotes a population of initiated cells with reduced levelsof transforming growth factor-P (TGFP) receptors types I,II and III. Liver tumors were induced in male Fischer F344rats by diethylnitrosamine (DEN). Following inductionthe animals were divided into PB-treated (DEN/PB) anduntreated groups (DEN). After 3 months of treatment halfof the PB-treated rats were removed from PB for the finalmonth (DEN/PB/OFF). At 4 months, the livers from ratsin the three treatment groups were removed, tumors excisedand frozen with matched surrounding normal tissue. ThemRNA levels for the TGFp receptors types I-HI weresignificantly decreased in tumor tissue from DEN/PB ratswhen compared with surrounding normal liver tissue ortumors from age-matched untreated controls. In tumorsfrom DEN/PB/OFF rats the TGFp receptor types I-mwere also significantly reduced compared with controls andnot different to tumors from DEN/PB rats. There was nodifference in the mRNA levels for the TGFP receptors intumors from rats exposed to DEN alone, when comparedwith the surrounding normal tissue. These results demon-strate that PB selectively promotes initiated cells withreduced levels of TGFP types I-HI receptors and suggestsa mechanistic role for TGFp in PB-induced liver tumorpromotion.Approximately 60% of the chemicals determined by theNational Toxicology Program to be carcinogenic in rats andmice give rise to liver tumors. Some of these carcinogens,however, are either only weakly genotoxic or have been foundto cause no detectable genetic damage. Rather, they appear tofunction as tumor promoting agents. These agents includechemicals to which humans are exposed, e.g. contraceptivesteroids (1,2), tamoxifen (3), benzodiazepine compounds (4),dioxin (5), and phenobarbital (PB*) (6). Although there is nodefinitive mechanism for the carcinogenic activity of thesediverse agents, one hypothesis involves reduced reponsivenessto negative growth signals, especially the potent mitoinhibitortransforming growth factor-P (TGFP) (7).In mammals TGFP exists as three highly homologousisoforms, TGFpi, TGFP2 and TGFP3 (8). These structurally