Acetylator genotype-dependent formation of 2-aminofluorene-hemoglobin adducts in rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus.
Arylamine-hemoglobin adducts are a valuable dosimeter for assessing arylamine exposures and carcinogenic risk. The effects of age, sex, time-course, dose, and acetylator genotype on levels of 2-aminofluorene-hemoglobin adducts were investigated in homozygous rapid (Bio. 82.73/H-Patr) and slow (Bio. 82.73/H-Pats) acetylator hamsters congenic at the polymorphic (NAT2) acetylator locus. Following administration of a single ip dose of [3H]2-aminofluorene, peak 2-aminofluorene-hemoglobin adduct levels were achieved at 12-18 hr and retained a plateau up to 72 hr postinjection in both rapid and slow acetylator congenic hamsters. 2-Aminofluorene-hemoglobin adduct levels did not differ significantly between young (5-6 weeks) and old (32-49 weeks) hamsters or between male and female hamsters within either acetylator genotype. 2-Aminofluorene-hemoglobin adduct levels increased in a dose-dependent manner (r = 0.95, p = 0.0001) and were consistently higher in slow versus rapid acetylator congenic hamsters in studies of both time-course and dose-effect. The magnitude of the acetylator genotype-dependent difference was a function of dose; 2-aminofluorene-hemoglobin adduct levels were 1.5-fold higher in slow acetylator congenic hamsters following a 60 mg/kg 2-aminofluorene dose (p = 0.0013) but 2-fold higher following a 100 mg/kg 2-aminofluorene dose (p < 0.0001). These results show a specific and significant role for NAT2 acetylator genotype in formation of arylamine-hemoglobin adducts, which may reflect the relationship between acetylator genotype and the incidence of different cancers from arylamine exposures.
Feng
Y
Y
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, Grand Forks 58202-9037.
Rustan
T D
TD
Ferguson
R J
RJ
Doll
M A
MA
Hein
D W
DW
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics*; D000367:Age Factors; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D005449:Fluorenes / Q000633:toxicity*; D005838:Genotype; D006454:Hemoglobins / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus / Q000235:genetics*; D012737:Sex Factors
D002273:Carcinogens; D005449:Fluorenes; D006454:Hemoglobins; C012177:2-aminofluorene; D000123:Acetyltransferases