DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ

Abstract

Epidemiological studies indicate that rapid acetylators with a high intake of well-done red meat have an increased risk of colorectal cancer. Arylamine N-acetyltransferase enzymes (E.C. 2.3.1.5) activate carcinogenic heterocyclic amines found in the crust of fried meat via O-acetylation of their N-hydroxylamines to reactive intermediates that bind covalently to DNA and produce mutations. Syrian hamsters as well as humans express two N-acetyltransferase isozymes (NAT1 and NAT2) which differ in substrate specificity and genetic control. Nucleic acid substitutions in the NAT2 gene segregate individuals into rapid, intermediate and slow acetylator phenotypes. In the present paper, we examined the role of the polymorphic NAT2 acetylator genotype in carcinogenesis induced by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by comparing Syrian hamster lines congenic at the NAT2 locus. No differences were found between rapid and slow acetylator congenic hamsters in levels of intestinal PhIP-DNA adducts. In contrast to previous studies in rats, no carcinogen-related induction of the preneoplastic lesions aberrant crypt foci or tumors was found in the intestines of rapid and slow acetylator congenic Syrian hamsters administered PhIP or IQ.

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

“…Significant differences were not observed in PhIP-DNA adduct levels between female rapid and slow acetylator congenic hamsters at the high doses of PhIP (100 mg/kg) used in this study. This finding is consistent with previous studies reporting no differences in 3,2Ј-dimethyl-4-aminobiphenyl [32] and PhIP-DNA [33] adduct levels between male rapid and slow acetylator congenic hamsters.…”

“…However, the high (10 doses of 75 mg/kg) PhIP-dosing regimen and high-fat diet used in our study was modeled after those that induce tumors from PhIP in the rat [5]. The lack of colon tumors observed in the PhIP-treated female Syrian hamsters, even when maintained on a high-fat diet for a year, is consistent with the relative lack of tumors recently reported in male Syrian hamsters administered PhIP [33].…”

Metabolism and Biomarkers of Heterocyclic Aromatic Amines in Molecular Epidemiology Studies: Lessons Learned from Aromatic Amines

“…In adult female rapid and slow acetylator rats congenic at the NAT2 locus, PhIP-DNA adduct formation was unaffected by NAT2 acetylator status in the liver or any of the extrahepatic tissue examined, whereas MeIQx-DNA adducts, particularly in the liver, were significantly lower in slow acetylators . Similar findings were observed in congenic rapid and slow acetylator Syrian hamsters; PhIP-DNA adduct formation was independent of N -acetylator activity . These data signify that PhIP genotoxicity in rodents is not influenced by NAT enzymes.…”

Effect of N-Acetyltransferase 2 Polymorphism on Tumor Target Tissue DNA Adduct Levels in Rapid and Slow Acetylator Congenic Rats Administered 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline

“…Furthermore, no differences in PhIP-DNA adduct levels were observed between rapid and slow acetylator congenic hamsters in colon or other tissues (Steffensen et al, 2000; Fretland et al, 2001a,b). Previous studies of PhIP-DNA adduct formation in the parental F344 and WKY parent inbred rat strains administered a diet containing 0.04% PhIP also showed higher levels of PhIP DNA adducts in the colon than the liver with significantly higher levels in F344 than WKY inbred rats (Purewal et al, 2000).…”