A hepatocarcinogenic tryptophan-pyrolyzate component, Trp-P-1, decreases serum total testosterone level and induces hepatic Cyp1a2 in male mice.
Male (BALB/c x DBA/2) F(1) mice were given 3-amino-1,4-dimethyl-5H-pyrido [4,3-b] indole acetate (Trp-P-1; 20 mg/kg body weight) by gavage at 24-h intervals for 1 or 2 weeks, and the effects of Trp-P-1 on the levels of serum total testosterone and hepatic cytochrome P4501a2 (Cyp1a2) were examined. A significant decrease in serum total testosterone level was observed after treatment with Trp-P-1 for 2 weeks, but not for 1 week. Likewise, gene expression levels of testicular androgenic enzymes, including cholesterol side chain cleavage cytochrome P450, 3beta-hydroxysteroid dehydrogenase and steroid 17alpha-hydroxylase/C17-20 lyase, decreased only in the mice treated with Trp-P-1 for 2 weeks. In contrast, levels of the mRNA and apoprotein of hepatic Cyp1a2 and its enzyme activity for O-demethylation of methoxyresorufin significantly increased in the mice treated with Trp-P-1 for 2 weeks, but only a small increase was observed in mice treated for 1 week. In the present study, we demonstrate for the first time that treatment of male mice with Trp-P-1 results in a decrease in serum total testosterone level through suppression of the gene expression of testicular enzymes responsible for androgen biosynthesis, and this then leads to induction of hepatic Cyp1a2.
Degawa
Masakuni
M
Department of Molecular Toxicology and the COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. degawa@smail.u-shizuoka-ken.ac.jp
Hanaki
Koji
K
Sekimoto
Masashi
M
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000818:Animals; D001059:Apoproteins / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000097:blood*
D001059:Apoproteins; D002243:Carbolines; D002273:Carcinogens; D012333:RNA, Messenger; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D019388:Cytochrome P-450 CYP1A2; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole