Strain-dependent effects of phenobarbital on liver tumor promotion in inbred mice

Inbred strains of mice were found to differ significantly in their susceptibility to liver tumor promotion by PB. The susceptibility to promotion of hepatocarcinogenesis by this drug was a dominant trait in crosses between the sensitive DBA and resistant C57 mice. The reciprocal F1 hybrids responded similarly to tumor promotion by PB. PB promoted the development of hepatoblastomas in D2B6F1 males but not in B6D2F1 mice. Female mice of the D2B6F1 cross, similarly exposed to PB, failed to develop hepatoblastomas. These results suggested a sex-linked differential response to the development of hepatoblastomas in reciprocal F1 hybrids that are genetically identical except for the reverse origin of their X and Y chromosomes. Differences in the promoting effects of PB between C57 and DBA mice appeared to correlate with differences in the metabolism/detoxification of this drug. In conclusion, mouse strains that differ in susceptibility to two-stage liver carcinogenesis provide excellent opportunities to investigate the genetic and/or biochemical mechanisms responsible for these differences. Understanding these mechanisms may lead to the identification of factors that affect liver tumor development not only in mice but in other species as well.