Cytochrome P-450 and acetyltransferase expression as biomarkers of carcinogen-DNA adduct levels and human cancer susceptibility.

A F Badawi, S J Stern, N P Lang, F F Kadlubar
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Abstract

Carcinogen-DNA adducts are generally regarded as relevant biomarkers of carcinogen exposure and their levels in target tissues have often been predictive of tumor incidence in experimental animals. Thus, human risk assessment procedures have utilized dose-response models that assume proportional relationships between carcinogen exposure and cancer susceptibility, even though wide inter-individual variations in human metabolic activating enzymes have now been clearly established. To evaluate these approaches, we have examined the relationship between carcinogen exposure, DNA adduct levels, metabolic activation phenotypes, and cancers of the larynx, urinary bladder, and colon. Cigarette smoking is a strong risk factor for cancers of the larynx and urinary bladder. In the larynx, the DNA adducts appear to be derived predominantly from polycyclic aromatic hydrocarbons (PAHs) and are evident only in tissue from smokers. However, adduct levels appear to be determined primarily by expression of cytochrome P450 (CYP) 2C9/10, which varies > 10-fold in different individuals. This CYP catalyzes the metabolic activation of benzo (alpha) pyrene (BP) to a 9-hydroxy-BP-DNA adduct that accounts for up to 25% of the putative PAH adducts formed in vivo. For the urinary bladder, putative aromatic amine (AA)-DNA adducts are predominant and are significantly elevated in current smokers. Rapid CYP1A2 and slow acetyltransferase (NAT2) phenotypes have been previously implicated in the activation (N-oxidation) and detoxification (N-acetylation) of AAs for human bladder carcinogenesis. Data now indicate that NAT1, which is expressed in human urothelium and catalyzes the O-acetylation of N-hydroxy arylamines, is significantly correlated with DNA adduct levels and is bimodally distributed in this tissue. Colo-rectal cancer risk, which has been associated with exposure to heterocyclic amines (HAs) in cooked foods, is strongly elevated in individuals with the combined rapid phenotypes for CYP1A2 and NAT2. These enzymes are uniquely responsible for HA N-oxidation and subsequent O-acetylation, forming DNA adducts that are found in human colon. These studies indicate that cancer risk assessment procedures should be redesigned to include biomarkers of susceptibility, especially those involved in carcinogen bioactivation.

细胞色素P-450和乙酰转移酶表达作为致癌- dna加合物水平和人类癌症易感性的生物标志物。
致癌物质- dna加合物通常被认为是致癌物质暴露的相关生物标志物,其在靶组织中的水平经常被用来预测实验动物的肿瘤发病率。因此,人类风险评估程序使用了剂量-反应模型,该模型假定致癌物暴露与癌症易感性之间存在比例关系,尽管现在已经清楚地确定了人类代谢激活酶的广泛个体间差异。为了评估这些方法,我们研究了致癌物质暴露、DNA加合物水平、代谢激活表型与喉癌、膀胱癌和结肠癌之间的关系。吸烟是喉癌和膀胱癌的一大危险因素。在喉部,DNA加合物似乎主要来自多环芳烃(PAHs),并且仅在吸烟者的组织中明显存在。然而,加合物水平似乎主要由细胞色素P450 (CYP) 2C9/10的表达决定,在不同个体中差异大于10倍。该CYP催化苯并(α)芘(BP)代谢激活为9-羟基BP- dna加合物,占体内形成的假定多环芳烃加合物的25%。对于膀胱,假定的芳香胺(AA)-DNA加合物占主导地位,并且在当前吸烟者中显着升高。快速CYP1A2和缓慢乙酰转移酶(NAT2)表型先前与人类膀胱癌发生中AAs的激活(n -氧化)和解毒(n -乙酰化)有关。目前的数据表明,NAT1在人尿路上皮中表达并催化n -羟基芳胺的o -乙酰化,与DNA加合物水平显著相关,并在该组织中呈双峰分布。与暴露于熟食中的杂环胺(has)有关的结直肠癌风险,在CYP1A2和NAT2联合快速表型的个体中显著升高。这些酶是唯一负责HA n氧化和随后的o -乙酰化,形成在人类结肠中发现的DNA加合物。这些研究表明,癌症风险评估程序应该重新设计,以包括易感性的生物标志物,特别是那些涉及致癌物生物活化的生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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