Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK.
Discovery Safety and Metabolism, AstraZeneca, Cambridge, CB4 0WG, UK.
Arch Toxicol. 2018 Apr;92(4):1639-1655. doi: 10.1007/s00204-018-2160-9. Epub 2018 Jan 23.
Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10-10 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α-) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10-10 M) with PhIP (10-10 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices.
食用熟肉和乙醇是乳腺癌病因学中的生活方式风险因素。烹饪肉类会产生杂环胺，如 2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）。流行病学、机制和动物研究表明，PhIP 是一种乳腺致癌物，可能与乳腺癌的发病率有关；PhIP 具有 DNA 损伤、致突变和雌激素活性。PhIP 毒性涉及细胞色素 P450（CYP1 家族）介导的代谢激活为 DNA 损伤物质，以及通过芳香烃受体（AhR）和雌激素受体-α（ER-α）的转录反应。乙醇的摄入是一种可改变的生活方式因素，与乳腺癌的风险密切相关。乙醇毒性涉及乙醇脱氢酶代谢为反应性乙醛，也是 CYP2E1 的底物，当 CYP2E1 解偶联时会产生活性氧（ROS）和 DNA 损伤。在这里，我们使用雌激素受体状态不同的人乳腺细胞，探讨了 PhIP 和乙醇的遗传毒性及其毒性背后的机制。用 PhIP（10-10 M）处理可显著诱导人乳腺细胞系（MCF-7，ER-α+）的遗传毒性（微核形成），而不是 MDA-MB-231（ER-α-）细胞。PhIP 诱导了两种细胞系中的 CYP1A2，但仅在 ER-α+细胞中选择性诱导了 CYP1B1。MCF-7 细胞中 ER-α 的抑制减弱了 PhIP 介导的微核形成和 CYP1B1 诱导。PhIP 通过 ER-α-STAT-3 途径诱导 CYP2E1 和 ROS，但仅在 ER-α+ MCF-7 细胞中。重要的是，与单独使用这些化学物质相比，生理浓度的乙醇（10-10 M）与 PhIP（10-10 M）同时处理会增加 MCF-7 细胞的氧化应激和遗传毒性。总的来说，这些数据为与饮食中熟肉和乙醇生活方式选择相关的乳腺癌风险增加提供了机制基础。
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