The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.
The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.
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NAT2 活性的个体差异对暴露工人中联苯胺尿代谢物和尿路上皮 DNA 加合物的影响。
DOI：
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发表时间：
1996
影响因子：
11.1
通讯作者：
G. Talaska
中科院分区：
文献类型：
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作者：
N. Rothman;V. K. Bhatnagar;R. Hayes;T. Zenser;S. Kashyap;M. Butler;D. Bell;V. Lakshmi;M. Jaeger;R. Kashyap;A. Hirvonen;P. Schulte;M. Dosemeci;F. Hsu;D. J. Parikh;B. Davis;G. Talaska
一些流行病学研究表明，NAT 2相关的缓慢N-乙酰化增加了接触芳香胺的工人患膀胱癌的风险，这可能是因为N-乙酰化对这些化合物的解毒很重要。以前，我们表明，NAT 2多态性并没有影响膀胱癌的风险，中国工人暴露于联苯胺（BZ），这表明NAT 2 N-乙酰化不是一个关键的解毒途径，这种芳香胺。为了评估这一发现的生物学可接受性，我们在印度的阿赫梅达巴德对33名接触BZ的工人和15名未接触BZ的对照者进行了一项横断面研究，以评估脱落的尿路上皮细胞中BZ相关DNA加合物的存在、BZ代谢物的排泄模式以及NAT 2活性对这些结果的影响。与对照组相比，暴露工人中的四种DNA加合物显著升高;其中，主要加合物与合成的N-（3 '-磷酸脱氧鸟苷-8-基）-N'-乙酰联苯胺标准品共层析，并且是唯一与总BZ尿代谢物显著相关的加合物（r = 0.68，P < 0.0001）。据我们所知，这是第一份报告表明，BZ形成DNA加合物在脱落的尿路上皮细胞暴露的人，形成的主要加合物是N-乙酰化，支持的概念，单官能乙酰化是一个激活，而不是解毒，步骤BZ。然而，由于几乎所有的苯并咪唑相关的代谢物在接触工人的尿液中被乙酰化，以及快速，乙酰化（平均值+/- SD分别为95 +/- 1.9%和97 +/-1.6%）和NAT 2活性不影响测量的任何DNA加合物的水平，NAT 2功能个体间差异与BZ相关的膀胱癌发生不太可能相关。
Several epidemiologic studies indicate that NAT2-related slow N-acetylation increases bladder cancer risk among workers exposed to aromatic amines, presumably because N-acetylation is important for the detoxification of these compounds. Previously, we showed that NAT2 polymorphisms did not influence bladder cancer risk among Chinese workers exposed exclusively to benzidine (BZ), suggesting that NAT2 N-acetylation is not a critical detoxifying pathway for this aromatic amine. To evaluate the biologic plausibility of this finding, we carried out a cross-sectional study of 33 workers exposed to BZ and 15 unexposed controls in Ahmedabad, India, to evaluate the presence of BZ-related DNA adducts in exfoliated urothelial cells, the excretion pattern of BZ metabolites, and the impact of NAT2 activity on these outcomes. Four DNA adducts were significantly elevated in exposed workers compared to controls; of these, the predominant adduct cochromatographed with a synthetic N-(3'- phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine standard and was the only adduct that was significantly associated with total BZ urinary metabolites (r = 0.68, P < 0.0001). To our knowledge this is the first report to show that BZ forms DNA adducts in exfoliated urothelial cells of exposed humans and that the predominant adduct formed is N-acetylated, supporting the concept that monofunctional acetylation is an activation, rather than a detoxification, step for BZ. However, because almost all BZ-related metabolites measured in the urine of exposed workers were acetylated among slow, as well as rapid, acetylators (mean +/- SD 95 +/- 1.9% vs. 97 +/- 1.6%, respectively) and NAT2 activity did not affect the levels of any DNA adduct measured, it is unlikely that interindividual variation in NAT2 function is relevant for BZ-associated bladder carcinogenesis.