Badawi A F, Stern S J, Lang N P, Kadlubar F F
National Center for Toxicological Research, Jefferson, AR 72079, USA.
Prog Clin Biol Res. 1996;395:109-40.
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.
致癌物 - DNA加合物通常被视为致癌物暴露的相关生物标志物，其在靶组织中的水平常常可预测实验动物的肿瘤发生率。因此，人类风险评估程序采用了剂量 - 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，尽管现已明确人类代谢激活酶存在广泛的个体差异。为了评估这些方法，我们研究了致癌物暴露、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个重要危险因素。在喉组织中，DNA加合物似乎主要来源于多环芳烃（PAH），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，该酶在不同个体中的表达差异超过10倍。这种CYP催化苯并（α）芘（BP）代谢活化为9 - 羟基 - BP - DNA加合物，该加合物占体内形成的假定PAH加合物的比例高达25%。对于膀胱组织，假定的芳香胺（AA） - DNA加合物占主导地位，且在当前吸烟者中显著升高。快速的CYP1A2和缓慢的乙酰转移酶（NAT2）表型先前已被认为与人类膀胱癌发生过程中AA的激活（N - 氧化）和解毒（N - 乙酰化）有关。目前的数据表明，在人类尿路上皮中表达并催化N - 羟基芳胺O - 乙酰化的NAT1与DNA加合物水平显著相关，且在该组织中呈双峰分布。与食用熟食中杂环胺（HA）暴露相关的结直肠癌风险，在具有CYP1A2和NAT2快速联合表型的个体中显著升高。这些酶专门负责HA的N - 氧化及随后的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重新设计，以纳入易感性生物标志物，尤其是那些参与致癌物生物激活的标志物。
