Mokhosoev Innokenty M, Astakhov Dmitry V, Terentiev Alexander A, Moldogazieva Nurbubu T
Independent Researcher, 108815 Moscow, Russia.
Department of Biochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia.
Cells. 2024 Nov 26;13(23):1958. doi: 10.3390/cells13231958.
Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs.
In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug-drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by gene polymorphisms, although a significant portion of them have no effects. However, polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated.
The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy.
细胞色素P450（CYPs）是一类含血红素的氧化还原酶，具有单加氧酶活性。人类CYPs可催化多种化学物质的氧化反应，包括外源性物质、甾体激素、维生素、胆汁酸、前致癌物和药物。
在我们的综述文章中，我们讨论了近期的数据，这些数据表明同一CYP同工酶可参与生物活化和解毒反应，并将同一底物转化为不同产物。相反，不同的CYP同工酶可将同一底物（外源性物质或前致癌物）转化为毒性更强或更弱的产物。这些现象取决于催化反应的类型、底物、组织类型和生物物种。由于参与生物活化的CYPs（CYP3A4、CYP1A1、CYP2D6和CYP2C8）主要在肝脏中表达，它们的代谢产物可诱导肝毒性和肝癌发生。此外，我们还讨论了药物作为CYP底物、诱导剂和抑制剂的作用，以及核受体、外排转运体和药物-药物相互作用在抗癌药物耐药性中的影响。我们强调了激素敏感性癌症（包括乳腺癌、卵巢癌、子宫内膜癌和前列腺癌）发生发展的分子机制。这些机制中的关键因素是雌激素的2,3-和3,4-儿茶酚，它们由CYP1A1、CYP1A2和CYP1B1形成。儿茶酚还可产生醌类物质，导致形成有毒的蛋白质和DNA加合物，从而促进癌症进展。然而，2-羟基和4-羟基雌激素及其O-甲基化衍生物以及结合代谢产物具有抗癌保护作用。参与睾酮前体生物合成的CYP17A1和CYP11A1与前列腺癌的发生有关，而睾酮转化为5α-二氢睾酮以及雄激素受体的持续激活和突变与转移性去势抵抗性前列腺癌（CRPC）有关。CYP酶活性受基因多态性影响，尽管其中很大一部分没有影响。然而，多态性可决定代谢不良、中等、快速和超快代谢基因型，这可影响癌症和药物易感性。尽管具有统计学意义的数据有限，但已证实不同人群中多态性与癌症风险、肿瘤大小和转移状态之间存在关联。
CYPs代谢多样性和生物效应的双重特性是其在激素敏感性癌症中发挥作用的基础。CYP活性和基因多态性的变化与癌症和药物易感性的个体差异有关。CYP抑制剂的开发为个性化抗癌治疗提供了选择。
