Probst-Hensch N M, Bell D A, Watson M A, Skipper P L, Tannenbaum S R, Chan K K, Ross R K, Yu M C
Institute of Social and Preventive Medicine of the University of Basel, Switzerland.
Cancer Epidemiol Biomarkers Prev. 2000 Jun;9(6):619-23.
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 (NAT110 allele) is associated with increased DNA adduct levels in urothelial tissue and higher risk of bladder cancer among smokers. It is not known whether NAT110 genotype influences ABP-hemoglobin adduct levels. Therefore, we assessed 403 primarily non-Hispanic white residents of Los Angeles County for their NAT2 acetylator phenotype, NAT110 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 NAT110 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.
烟草中的氨基联苯（ABP）与吸烟者膀胱癌的病因有关。肝脏中ABP的N - 乙酰化主要由N - 乙酰基转移酶2（NAT2）同工酶介导，这是一条解毒途径；而膀胱中N - 羟基 - ABP的O - 乙酰化主要由N - 乙酰基转移酶1（NAT1）同工酶介导，这是一条生物活化途径。我们和其他人已经证明，NAT2表型会影响3 - 和4 - ABP - 血红蛋白加合物水平（慢乙酰化者中的水平更高），这些加合物被认为是ABP进入膀胱内剂量的有效生物标志物。我们还表明，NAT1基因型（NAT110等位基因）与尿路上皮组织中DNA加合物水平升高以及吸烟者患膀胱癌的风险增加有关。尚不清楚NAT110基因型是否会影响ABP - 血红蛋白加合物水平。因此，我们对洛杉矶县的403名主要为非西班牙裔白人居民进行了评估，检测他们的NAT2乙酰化表型、NAT110乙酰化基因型以及3 - 和4 - ABP - 血红蛋白加合物水平。82名受试者为不同吸烟强度的现吸烟者。吸烟者的3 - 和4 - ABP - 血红蛋白平均加合物水平显著高于非吸烟者。加合物水平随每日吸烟量增加而升高（双侧检验在所有情况下P < 0.0001）。在对NAT1基因型和种族进行调整后，NAT2慢乙酰化者中3 - ABP - 血红蛋白加合物的吸烟调整几何平均水平比NAT2快乙酰化者高47%（P = 0.01）。4 - ABP - 血红蛋白加合物的可比数值为高17%（P = 0.02）。相比之下，在对NAT2表型、吸烟和种族进行调整后，未观察到NAT110基因型与3 - 或4 - ABP - 血红蛋白加合物水平之间存在关联。本研究表明，NAT1*10基因型对3 - 和4 - ABP - 血红蛋白加合物的影响对于NAT1活性与膀胱癌风险之间可能存在的关联并无参考价值。
