Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
Adv Exp Med Biol. 2018;1032:15-35. doi: 10.1007/978-3-319-98788-0_2.
Cytochrome P450 (P450) enzymes are involved in the metabolism of carcinogens, as well as drugs, steroids, vitamins, and other classes of chemicals. P450s also oxidize ethanol, in particular P450 2E1. P450 2E1 oxidizes ethanol to acetaldehyde and then to acetic acid, roles also played by alcohol and aldehyde dehydrogenases. The role of P450 2E1 in cancer is complex in that P450 2E1 is also induced by ethanol, P450 2E1 is involved in the bioactivation and detoxication of a number of chemical carcinogens, and ethanol is an inhibitor of P450 2E1. Contrary to some literature, P450 2E1 expression and induction itself does not cause global oxidative stress in vivo, as demonstrated in studies using isoniazid treatment and gene deletion studies with rats and mice. However, a major fraction of P450 2E1 is localized in liver mitochondria instead of the endoplasmic reticulum, and studies with site-directed rat P450 2E1 mutants and natural human P450 2E1 N-terminal variants have shown that P450 2E1 localized in mitochondria is catalytically active and more proficient in producing reactive oxygen species and damage. The role of the mitochondrial oxidative stress in ethanol toxicity is still under investigation, as is the mechanism of altered electron transport to P450s that localize inside mitochondria instead of their typical endoplasmic reticulum environment.
细胞色素 P450（P450）酶参与致癌物、药物、类固醇、维生素和其他化学物质的代谢。P450 还氧化乙醇，特别是 P450 2E1。P450 2E1 将乙醇氧化为乙醛，然后氧化为乙酸，这也是醇脱氢酶和醛脱氢酶的作用。P450 2E1 在癌症中的作用很复杂，因为乙醇也能诱导 P450 2E1，P450 2E1 参与了许多化学致癌物的生物活化和解毒作用，而乙醇是 P450 2E1 的抑制剂。与一些文献相反，P450 2E1 的表达和诱导本身并不会在体内引起全身性氧化应激，这在使用异烟肼治疗和大鼠和小鼠基因缺失研究中得到了证明。然而，很大一部分 P450 2E1 位于肝线粒体而不是内质网中，并且使用靶向大鼠 P450 2E1 突变体和天然人类 P450 2E1 N 端变体的研究表明，位于线粒体中的 P450 2E1 具有催化活性，并且更擅长产生活性氧和损伤。线粒体氧化应激在乙醇毒性中的作用仍在研究中，以及将定位在内质网环境中的 P450 转移到线粒体中的电子传递机制也在研究中。
