Interstrain differences in susceptibility to liver carcinogenesis initiated by N-nitrosodiethylamine and its promotion by phenobarbital in C57BL/6NCr, C3H/HeNCrMTV- and DBA/2NCr mice

Selected inbred strains of mice were compared with respect totheir susceptibility to two-stage liver carcinogenesis. Five-week-oldmale mice of strains C57BL/6NCr (C57), C3H/HeNCr^MTV- (C3H) andDBA/2NCr (DBA) were given a single i.p. injection of N-nitrosodiethylamine(DEN, 90 mg/kg body weight) or the solvent tricaprylin (10 ml/kg).Beginning 2 weeks later, half of the DEN-treated and half ofthe control mice were given drinking water containing 0.05%phenobarbital (PB). Ten mice from each treatment group werekilled at 12, 24, 36 and 52 weeks of age (5, 17, 29 and 45 weeksexposure to PB). PB significantly increased both the numberof hepatocellular foci/cm² and the incidence of hepatocellulartumors after 17 weeks of treatment in 24-week-old DEN-initiatedmice of strains C3H (0.11 ± 0.07 versus 2.9 ±0.3 foci/cm² and 20 versus 70% incidence of hepatocellular tumors)and DBA (0.09 ± 0.09 versus 3.72 ± 0.6 foci/cm²and 0 versus 90% incidence of hepatocellular tumors) but wasineffective in C57 mice (0.04 ± 0.04 versus 0.07 ±0.07 foci/cm²). At 36 weeks of age the incidence of liver celltumors in mice given DEN but not PB was 10 (DBA), 10 (C57) and50% (C3H); the incidence was increased by PB to 90% in DBA and100% in C3H mice, but there was no increase in C57 mice. Evenat 52 weeks, the low incidence of hepatocellular tumors in C57mice given DEN only (20%) was not significantly increased bysubsequent exposure to PB. Serum PB levels observed at 12, 24and 36 weeks of age were significantly higher in DBA mice thanin C57 or C3H mice. Similar results were observed in a separatestudy in which PB was administered in drinking water to 7-week-oldmale mice of these three strains for 20 days, during which periodserum PB levels were measured at shorter intervals. DBA micethus appear to be unable to metabolize PB, which itself ratherthan its metabolites is probably responsible for tumor-promotingeffects. DBA mice were especially sensitive, while C57 micewere refractory to promotion of hepatocar-cinogenesis by PB.These two strains, which differ with respect to other significantparameters for chemical carcinogenesis including inducibilityfor aryl hydrocarbon hydroxylase and susceptibility to promotionof hydrocarbon-initiated skin tumors by 12-O-tetradecanoyl-phorbol-13-acetate,thus also provide a means for analysis of the pharmacogeneticsof susceptibility to hepatocellular tumor promotion.