Premium
DNA adduct levels and absence of tumors in female rapid and slow acetylator congenic hamsters administered the rat mammary carcinogen 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐ b ]pyridine
Author(s) -
Fretland Adrian J.,
Devanaboyina Uday S.,
Nangju Norma A.,
Leff Matthew A.,
Xiao Gong H.,
Webb Stephanie J.,
Doll Mark A.,
Hein David W.
Publication year - 2001
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/1099-0461(2001)15:1<26::aid-jbt3>3.0.co;2-s
Subject(s) - heterocyclic amine , carcinogen , dna adduct , endocrinology , chemistry , medicine , sulfotransferase , biochemistry , biology , enzyme
N ‐acetyltransferases (EC 2.3.1.5) catalyze O ‐acetylation of heterocyclic amine carcinogens to DNA‐reactive electrophiles that bind and mutate DNA. An acetylation polymorphism exists in humans and Syrian hamsters regulated by N ‐acetyltransferase‐2 (NAT2) genotype. Some human epidemiological studies suggest a role for NAT2 phenotype in predisposition to cancers related to heterocyclic amine exposures, including breast cancer. 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐ b ]pyridine (PhIP) is a heterocyclic amine carcinogen prevalent in the human environment and induces a high incidence of mammary tumors in female rats. PhIP‐induced carcinogenesis was examined in female rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus. In both rapid and slow acetylators, PhIP‐DNA adduct levels were highest in pancreas, lower in heart, small intestine, and colon, and lowest in mammary gland and liver. Metabolic activation of N ‐hydroxy‐PhIP by O ‐acetyltransferase was highest in mammary epithelial cells, lower in liver and colon, and lowest in pancreas. Metabolic activation of N ‐hydroxy‐PhIP by O ‐sulfotransferase was low in liver and colon and below the limit of detection in mammary epithelial cells and pancreas. Unlike the rat, PhIP did not induce breast or any other tumors in female rapid and slow acetylator congenic hamsters administered high‐dose PhIP (10 doses of 75 mg/kg) and a high‐fat diet. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:26–33, 2001