Lung cancer has the second highest incidence and highest mortality compared to all other cancers. Polycyclic aromatic hydrocarbon (PAH) molecules belong to a class of compounds that are present in tobacco smoke, diesel exhausts, smoked foods, as well as particulate matter (PM). PAH-derived reactive metabolites are significant contributors to lung cancer development. The formation of these reactive metabolites entails metabolism of the parent PAHs by cytochrome P4501A1/1B1 (CYP1A1/1B1) and epoxide hydrolase enzymes. These reactive metabolites then react with DNA to form DNA adducts, which contribute to key gene mutations, such as the tumor suppressor gene, p53 and are linked to pulmonary carcinogenesis. PAH exposure also leads to upregulation of CYP1A1 transcription by binding to the aryl hydrocarbon receptor (AHR) and eliciting transcription of the CYP1A1 promoter, which comprises specific xenobiotic-responsive element (XREs). While hepatic and pulmonary CYP1A1/1B1 metabolize PAHs to DNA-reactive metabolites, the hepatic CYP1A2, however, may protect against lung tumor development by suppressing both liver and lung CYP1A1 enzymes. Further analysis of these enzymes has shown that PAH-exposure also induces sustained transcription of CYP1A1, which is independent of the persistence of the parent PAH. CYP1A2 enzyme plays an important role in the sustained induction of hepatic CYP1A1. PAH exposure may further contribute to pulmonary carcinogenesis by producing epigenetic alterations. DNA methylation, histone modification, long interspersed nuclear element (LINE-1) activation, and non-coding RNA, specifically microRNA (miRNA) alterations may all be induced by PAH exposure. The relationship between PAH-induced enzymatic reactive metabolite formation and epigenetic alterations is a key area of research that warrants further exploration. Investigation into the potential interplay between these two mechanisms may lead to further understanding of the mechanisms of PAH carcinogenesis. These mechanisms will be crucial for the development of effective targeted therapies and early diagnostic tools.

与所有其他癌症相比，肺癌的发病率和死亡率位居第二。多环芳烃 (PAH) 分子属于存在于烟草烟雾、柴油机尾气、熏制食品以及颗粒物 (PM) 中的一类化合物。PAH 衍生的反应性代谢物是肺癌发展的重要因素。这些反应性代谢物的形成需要通过细胞色素 P4501A1/1B1 (CYP1A1/1B1) 和环氧化物水解酶对亲本 PAHs 进行代谢。这些反应性代谢物然后与 DNA 反应形成 DNA 加合物，这些加合物导致关键基因突变，例如肿瘤抑制基因 p53，并与肺癌发生有关。PAH 暴露还通过与芳烃受体 (AHR) 结合并引发 CYP1A1 启动子的转录，从而导致 CYP1A1 转录的上调，该启动子包含特定的外源性反应元件 (XRE)。虽然肝和肺 CYP1A1/1B1 将 PAHs 代谢为 DNA 反应性代谢物，但肝 CYP1A2 可以通过抑制肝和肺 CYP1A1 酶来防止肺肿瘤的发展。对这些酶的进一步分析表明，PAH 暴露还诱导 CYP1A1 的持续转录，这与亲本 PAH 的持久性无关。CYP1A2 酶在肝脏 CYP1A1 的持续诱导中起重要作用。PAH 暴露可能通过产生表观遗传改变进一步促进肺癌的发生。DNA甲基化、组蛋白修饰、长散在的核元件 (LINE-1) 激活和非编码 RNA，特别是 microRNA (miRNA) 的改变都可能由 PAH 暴露引起。PAH 诱导的酶促反应性代谢物形成与表观遗传改变之间的关系是值得进一步探索的关键研究领域。对这两种机制之间潜在相互作用的调查可能会导致对 PAH 致癌机制的进一步了解。这些机制对于开发有效的靶向治疗和早期诊断工具至关重要。PAH 诱导的酶促反应性代谢物形成与表观遗传改变之间的关系是值得进一步探索的关键研究领域。对这两种机制之间潜在相互作用的调查可能会导致对 PAH 致癌机制的进一步了解。这些机制对于开发有效的靶向治疗和早期诊断工具至关重要。PAH 诱导的酶促反应性代谢物形成与表观遗传改变之间的关系是值得进一步探索的关键研究领域。对这两种机制之间潜在相互作用的调查可能会导致对 PAH 致癌机制的进一步了解。这些机制对于开发有效的靶向治疗和早期诊断工具至关重要。