3-amino-1-4-dimethyl-5h-pyrido(4-3-b)indole and Body-Weight

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.

Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Apoproteins; Body Weight; Carbolines; Carcinogens; Cholesterol Side-Chain Cleavage Enzyme; Cytochrome P-450 CYP1A2; Gene Expression Regulation, Enzymologic; Liver; Male; Mice; Organ Size; RNA, Messenger; Steroid 17-alpha-Hydroxylase; Testis; Testosterone

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.

Topics: Animals; Body Weight; Carbolines; Carcinogens; Drug Synergism; Enzyme Induction; Glutathione Transferase; Imidazoles; Immunohistochemistry; Liver; Liver Neoplasms; Male; Organ Size; Quinolines; Quinoxalines; Rats; Rats, Inbred F344

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) or 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), which is a potent mutagen from pyrolysates of tryptophan, was given subcutaneously to neonatal ICR mice, and all animals were observed for 1 year. Tumors of the livers and lymphoreticular tissue were induced. In the mice given Trp-P-1, the incidences of these tumors were as follows: liver tumors in 45% of the males; malignant lymphoma in 13% of the males and in 24% of the females. In the mice given Trp-P-2, the incidences of liver tumors in the males were dose-dependent (12.5 mg/kg, 12%; 25 mg/kg, 18%), while those of malignant lymphoma varied within a range from 5 to 19%. Statistical analysis revealed that the incidences of the liver tumor in the mice given Trp-P-1 or Trp-P-2 and those of lymphoma in the mice given Trp-P-1 were significantly higher than those of the controls. In the control mice, the incidences of tumors were as follows: malignant lymphoma in 5% of the females; lung tumor in 14% of both sexes.

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Carbolines; Female; Liver Neoplasms, Experimental; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred ICR; Mutagens; Neoplasms, Experimental; Sex Factors