The food mutagen 2-amino-9H-pyrido[2,3-b]indole (AalphaC) but not its methylated form (MeAalphaC) increases intestinal tumorigenesis in neonatally exposed multiple intestinal neoplasia mice.
The heterocyclic amines 2-amino-9H-pyrido[2,3-b]indole (AalphaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) are carcinogenic in several organs in rodents, but not in the intestinal tract. However, AalphaC induces DNA adducts, mutations and preneoplastic aberrant crypt foci (ACF) in rodent colons. The purpose of this study was to examine whether AalphaC and MeAalphaC could affect intestinal tumorigenesis in C57BL/6J-Min/+ (multiple intestinal neoplasia) mice. These mice are heterozygous for a germline nonsense mutation in codon 850 of the tumor suppressor gene adenomatous polyposis coli (Apc), producing a truncated non-functional Apc protein. They develop multiple intestinal adenomas, and are particularly susceptible to intestinal carcinogens that affect the Apc gene, especially when exposed neonatally. Whole litters consisting of Min/+ and +/+ (wild-type) mice of both sexes were given a single s.c. injection of 0.22 mmol/kg AalphaC (40.3 mg/kg) or MeAalphaC (43.4 mg/kg) or the vehicle 1:1 dimethylsulfoxide:0.9% NaCl on days 3-6 after birth, and were terminated at 11 weeks. AalphaC increased the number and diameter of small intestinal tumors, but not the number of colonic tumors or dysplastic ACF, in female and male Min/+ mice separately. In pooled data from females and males, colonic tumors and ACF found after AalphaC exposure appeared to be smaller than the spontaneous lesions, indicating later induction, slower growth or both. In contrast to AalphaC, MeAalphaC did not affect intestinal tumorigenesis in Min/+ mice. No effects were found by any of the amino-alpha-carbolines in the +/+ mice. AalphaC was less potent than the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
Steffensen
Inger-Lise
IL
Department of Food Toxicology, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403, Oslo, Norway. inger-lise.steffensen@fhi.no
Paulsen
Jan Erik
JE
Alexander
Jan
J
D000818:Animals; D000831:Animals, Newborn; D002243:Carbolines / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005502:Food; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D007414:Intestinal Neoplasms / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*
D002243:Carbolines; D009153:Mutagens; C017822:2-amino-9H-pyrido(2,3-b)indole