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

Trp-P-2(3-amino-1-methyl-5H-pyrido [4,3-b] indole) ingestion for 42 d by C3H/HeJJcl mice caused elevation of serum alanine transaminase (ALT) activity and several signs of liver injury. These alterations were not observed in mice fed the diet supplemented with 10% miso. This suggests a preventive effect of miso as to Trp-P-2 induced liver injury.

Topics: Animals; Body Weight; Carbolines; Liver; Liver Diseases; Male; Mice; Organ Size; Soy Foods

Osteogenic Disorder Shionogi (ODS) rats, which cannot synthesize ascorbic acid due to a deficiency of L-gulonolactone oxidase, become scorbutic when not supplied with dietary ascorbic acid. We used the deficient rats to study the effects of ascorbic acid on the amount of cytochrome P450 enzymes in liver microsomes. The total amount of hepatic cytochrome P450 in ODS rats deprived of ascorbic acid was lower by approximately 40%, whereas ODS rats fed with ascorbic acid and the wild strain had the same level of total hepatic cytochrome P450. Western blot analysis for various forms of cytochrome P450 in liver microsomes indicated that the amount of CYP1A2 was significantly higher in ascorbic acid deficient rats. On the other hand, amounts of CYP2B2 and 3A were lower, and those of CYP2E1 and CYP2C6/11 were unaffected. In accordance with the higher amount of CYP1A2, Northern blot analysis showed increased expression of CYP1A2 mRNA. The capacity of microsomes to produce mutagens from 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole acetate (Glu-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate (Trp-P-2) was higher in scorbutic ODS rats by the Ames test. These results indicate that the effects of ascorbic acid deficiency on the expression of cytochrome P450 in ODS rat livers are form-specific and that the increased CYP1A2 is associated with increased metabolic activation of promutagens in the scorbutic state.

Topics: Animals; Ascorbic Acid Deficiency; Base Sequence; Biotransformation; Body Weight; Carbolines; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Electron Transport; Imidazoles; Male; Microsomes, Liver; Molecular Sequence Data; Mutagens; NADPH-Ferrihemoprotein Reductase; Oligonucleotide Probes; Organ Size; Oxidoreductases; Rats; Rats, Mutant Strains

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