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Sex-dependent Induction of Hepatic Enzymes for Mutagenic Activation of a Tryptophan Pyrolysate Component, 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]-indole, by Feeding in Mice¹

Department of Hygienic Chemistry, Pharmaceutical Institute, Tohoku University, Sendai 980, Japan

Male and female BALB/c x DBA/2 F₁ mice were treated with a diet containing 0.02% 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]-indole (Trp P-1), a hepatocarcinogenic tryptophan pyrolysate component, and the capacities of subcellular fractions of the liver to catalyze the mutagenic activation of Trp P-1 and its analogue Trp P-2 (4-demethylated Trp P-1) were examined by the in vitro Salmonella test with strain TA 98. In mice on control diet, both 9000 x g supernatant (S-9) and microsomal fractions from female mice livers displayed only 1.1- to 1.3-fold higher capacities for the mutagenic activation of either Trp P-1 or Trp P-2 than did those from male mice livers. When mice were treated with the Trp P-1 diet for 1 week, the S-9 activity in male mice for the Trp P-1 mutagenesis did not change, but that in females was increased to 2.5-fold of the female control. Treatment of mice with the dietary Trp P-1 for 2 weeks increased the S-9 activities to 2.8-fold in males and 4.9-fold in females of the same sex controls and the increased S-9 activities were not significantly changed by additional Trp P-1 feeding for 2 weeks. Similar changes in the S-9 activity were observed for the Trp P-2 mutagenesis. The overall changes in the S-9 activities induced by feeding Trp P-1 were reflected in the isolated microsomes. However, microsomes derived from the same volume of S-9 used exhibited only about one-half (Trp P-1) or one-third (Trp P-2) of the activity of the respective complete S-9 mixtures. Addition of liver cytosolic fractions (105,000 x g supernatants) from untreated or Trp P-1-treated mice to microsomes resulted in enhanced activities. Cytosols alone did not activate the compounds to mutagens.

The microsome-mediated mutagenicity of either Trp P-1 or Trp P-2 was diminished by removal of NADPH from the assay system. It was also inhibited by addition of 7,8-benzoflavone and to a lesser extent by SKF 525A. Enzyme(s) for the mutagenic activation of Trp P-1 was induced by an i.p. injection of 3-methylcholanthrene to mice and to a lesser extent by an injection of phenobarbital, but no sex differences were observed in these enzyme inductions as opposed to the Trp P-1 feeding.

The total cytochrome P-450 contents in liver microsomes were increased by the 2-week Trp P-1 feeding to 1.3-fold in males and 1.6-fold in females of the same sex controls, but no increased cytochrome P-450 contents were observed with the Trp P-1 feeding for 1 or 4 weeks. The changes of microsomal aniline p-hydroxylase activity followed the changes of the total cytochrome P-450 contents in the microsomes, but the activity of microsomal aminopyrine N-demethylase was not changed by the Trp P-1 feeding.

These findings indicate that the dietary Trp P-1 can selectively induce isotype(s) of microsomal cytochrome P-450, probably an isotype of cytochrome P-448, which catalyzes the mutagenic activation of Trp P-1, and that the induction of the carcinogen activation enzyme(s) in the initiation phase of the carcinogenesis may relate to the sex difference in the reported Trp P-1 carcinogenesis.

¹ Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture, Japan, and a grant from the Takeda Foundation, Japan.

² To whom requests for reprints should be addressed.

Received 7/18/83. Accepted 9/25/84.

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