Species, sex and organ differences in induction of a cytochrome P-450 isozyme responsible for carcinogen activation: effects of dietary hepatocarcinogenic tryptophan pyrolysate components in mice and rats.

Abstract

Both sexes of BALB/c X DBA/2 F1 mice and F344 rats were treated for 1 week with a diet containing 0.02% of hepatocarcinogenic tryptophan pyrolysate component (Trp P-1 or Trp P-2), and changes in the carcinogen activation enzyme activity in various organs were examined comparatively using a mutation test with Salmonella typhimurium TA98 as a tester bacterium. Hepatic enzymes from untreated mice and rats showed a definite catalytic activity for mutagenic activations of Trp P-1 and Trp P-2, whereas the activities of other organs--such as lung, kidney, small intestine and colon--were undetectable or very low. In both mice and rats either the Trp P-1 or Trp P-2 feeding resulted in induction of cytochrome P-450 isozyme(s), which could mediate in the liver but not in other organs the mutagenic activation of the carcinogen itself. As to the sex difference, the induction of the activation enzyme(s) was greater in the female animals than in the males. Species difference in the activity of hepatic enzymes catalyzing the Trp P-1 and Trp P-2 mutageneses was also observed in animals treated with the basal diet; the activity was higher in mice than in the sex-matched rats (Trp P-1, approximately 1.5-fold; Trp P-2, approximately 7-fold). When diet containing Trp P-1 or Trp P-2 was fed for 1 week, the activity of the rat liver for Trp P-1 mutagenesis was of a level similar to that of the sex-matched mice, but for Trp P-2 mutagenesis it was less than half that in the mice. The induced hepatic enzymes in mice and rats were suggested to be 3-methylcholanthrene-inducible cytochrome P-448 isozymes as determined by mutation tests with Trp P-1, Trp P-2 and two other substrates and by immunochemical analyses of rat hepatic cytochrome P-450 using monoclonal antibodies against rat cytochrome P-448 isozymes. These results indicate that a form of cytochrome P-450 responsible for activation of Trp P-1 and Trp P-2 is inducible by dietary treatment of mice or rats with these carcinogens and that the amount of the cytochrome P-450, including resident and induced forms, is related to the species, sex and organ differences in their carcinogenic susceptibility to these chemicals.