title: N-acetyltransferase 2 phenotype but not NAT1*10 genotype affects aminobiphenyl-hemoglobin adduct levels.
abstract: Aminobiphenyls (ABPs) in tobacco have been implicated in bladder cancer etiology in smokers. N-Acetylation of ABPs in the liver, predominantly by the N-acetyltransferase 2 (NAT2) isozyme, represents a detoxification pathway, whereas O-acetylation of N-hydroxy-ABPs in the bladder, predominantly by the N-acetyltransferase 1 (NAT1) isozyme, represents a bioactivation pathway. We and others have demonstrated that NAT2 phenotype affects 3- and 4-ABP-hemoglobin adduct levels (higher levels in slow acetylators), which are considered valid biomarkers of the internal dose of ABP to the bladder. We have also shown that NAT1 genotype (NAT1*10 allele) is associated with increased DNA adduct levels in urothelial tissue and higher risk of bladder cancer among smokers. It is not known whether NAT1*10 genotype influences ABP-hemoglobin adduct levels. Therefore, we assessed 403 primarily non-Hispanic white residents of Los Angeles County for their NAT2 acetylator phenotype, NAT1*10 acetylator genotype, and 3- and 4-ABP-hemoglobin adduct levels. Eighty-two subjects were current tobacco smokers of varying intensities. Tobacco smokers had significantly higher mean 3- and 4-ABP-hemoglobin adduct levels relative to nonsmokers. The levels increased with increased amounts smoked per day (two-sided, P < 0.0001 in all cases). With adjustment for NAT1 genotype and race, the smoking-adjusted geometric mean level of 3-ABP-hemoglobin adducts in NAT2 slow acetylators was 47% higher than that in NAT2 rapid acetylators (P = 0.01). The comparable value for 4-ABP-hemoglobin adducts was 17% (P = 0.02). In contrast, no association between NAT1*10 genotype and 3- or 4 ABP-hemoglobin adduct levels was observed after adjustment for NAT2 phenotype, smoking, and race. The present study suggests that the impact of the NAT1*10 genotype on 3- and 4-ABP-hemoglobin adducts is noninformative on the possible association between NAT1 activity and bladder cancer risk.
authors.affiliation: Institute of Social and Preventive Medicine of the University of Basel, Switzerland.
authors.forename: N M
authors.initials: NM
authors.lastname: Probst-Hensch
authors.forename: D A
authors.initials: DA
authors.lastname: Bell
authors.forename: M A
authors.initials: MA
authors.lastname: Watson
authors.forename: P L
authors.initials: PL
authors.lastname: Skipper
authors.forename: S R
authors.initials: SR
authors.lastname: Tannenbaum
authors.forename: K K
authors.initials: KK
authors.lastname: Chan
authors.forename: R K
authors.initials: RK
authors.lastname: Ross
authors.forename: M C
authors.initials: MC
authors.lastname: Yu
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000611:Aminobiphenyl Compounds / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D018736:DNA Adducts / Q000097:blood; D005260:Female; D005838:Genotype; D006454:Hemoglobins; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics*
chemical_list: D000611:Aminobiphenyl Compounds; D015415:Biomarkers; D018736:DNA Adducts; D006454:Hemoglobins; D000123:Acetyltransferases