Henkler Frank, Stolpmann Kristin, Luch Andreas
Department of Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany.
Exp Suppl. 2012;101:107-31. doi: 10.1007/978-3-7643-8340-4_5.
Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) have been intensively studied for decades. Although the genotoxicity of these compounds is well characterized (i.e., formation of bulky PAH-DNA adducts), molecular details on the DNA damage response triggered by PAHs in cells and tissues remain to be clarified. The conversion of hazardous PAHs into carcinogenic intermediates depends on enzyme-catalyzed biotransformation. Certain cytochrome P450-dependent monooxygenases (CYPs) play a pivotal role in PAH metabolism. In particular, CYP1A1 and 1B1 catalyze oxidation of PAHs toward primary epoxide species that can further be converted into multiple follow-up products, both nonenzymatically and enzymatically. Distinct functions between these major CYP enzymes have only been appreciated since transgenic animal models had been derived. Electrophilic PAH metabolites are capable of forming stable DNA adducts or to promote depurination at damaged nucleotide sites. During the following DNA replication cycle, bulky PAH-DNA adducts may be converted into mutations, thereby affecting hot spot sites in regulatory important genes such as Ras, p53, and others. Depending on the degree of DNA distortion and cell cycle progression, PAH-DNA adducts trigger nucleotide excision repair (NER) and various DNA damage responses that might include TP53-dependent apoptosis in certain cell types. In fact, cellular responses to bulky PAH-DNA damage are complex because distinct signaling branches such as ATM/ATR, NER, TP53, but also MAP kinases, interact and cooperate to determine the overall outcome to cellular injuries initiated by PAH-DNA adducts. Further, PAHs and other xenobiotics can also confer DNA damage via an alternative route of metabolic activation, which leads to the generation of PAH semiquinone radicals and reactive oxygen species (ROS). One-electron oxidations mediated by peroxidases or other enzymes can result in PAH radical cations that mainly form unstable DNA adducts subjected to depurination. In addition, generation of ROS can also trigger multiple cellular signaling pathways not directly related to mutagenic or cytotoxic effects, including those mediated by NFκB, SAPK/JNK, and p38. In recent years, it became clear that PAHs may also be involved in inflammatory diseases, autoimmune disorders, or atherosclerosis. Further research is under way to better characterize the significance of such newly recognized systemic effects of PAHs and to reconsider risk assessment for human health.
几十年来，人们对环境和饮食中的致癌物如多环芳烃（PAHs）进行了深入研究。尽管这些化合物的遗传毒性已得到充分表征（即形成大体积的PAH-DNA加合物），但PAHs在细胞和组织中引发的DNA损伤反应的分子细节仍有待阐明。有害PAHs转化为致癌中间体依赖于酶催化的生物转化。某些细胞色素P450依赖性单加氧酶（CYPs）在PAH代谢中起关键作用。特别是，CYP1A1和1B1催化PAHs氧化生成初级环氧化合物，这些环氧化合物可进一步通过非酶和酶促方式转化为多种后续产物。自从获得转基因动物模型以来，人们才认识到这些主要CYP酶之间的不同功能。亲电子PAH代谢产物能够形成稳定的DNA加合物或促进受损核苷酸位点的脱嘌呤作用。在随后的DNA复制周期中，大体积的PAH-DNA加合物可能会转化为突变，从而影响Ras、p53等调控重要基因中的热点位点。根据DNA扭曲程度和细胞周期进程，PAH-DNA加合物会触发核苷酸切除修复（NER）和各种DNA损伤反应，在某些细胞类型中可能包括TP53依赖性凋亡。事实上，细胞对大体积PAH-DNA损伤的反应很复杂，因为不同的信号分支如ATM/ATR、NER、TP53，还有丝裂原活化蛋白激酶相互作用并协同作用，以确定由PAH-DNA加合物引发的细胞损伤的总体结果。此外，PAHs和其他外源性物质也可通过代谢活化的替代途径导致DNA损伤，这会导致PAH半醌自由基和活性氧（ROS）的产生。过氧化物酶或其他酶介导的单电子氧化可产生PAH自由基阳离子，其主要形成不稳定的DNA加合物并发生脱嘌呤作用。此外，ROS的产生还可触发多种与诱变或细胞毒性效应不直接相关的细胞信号通路，包括由NFκB、SAPK/JNK和p38介导的信号通路。近年来，越来越清楚的是，PAHs也可能参与炎症性疾病、自身免疫性疾病或动脉粥样硬化。正在进行进一步研究，以更好地表征PAHs这种新认识的全身效应的重要性，并重新考虑对人类健康的风险评估。
