细胞色素CYP1B1:在癌症发生发展中作用的研究进展

Cytochrome CYP1B1: Research Advances on the Role in Carcinogenesis and Cancer Development

关键词:  CYP1B1  癌症  代谢激活  基因多态性  靶向治疗  药物耐药性

Key words:  CYP1B1  cancer  metabolic activation  genetic polymorphism  targeted therapy  drug resistance

摘要:

细胞色素P450(CYP)1B1作为肝外代谢的关键酶,在多种恶性肿瘤中呈现组织特异性高表达,而在正常组织中则低表达或不表达。该酶通过双重机制促进肿瘤的发生与发展:一方面,催化雌激素生成具有遗传毒性的4-羟基雌二醇,其后氧化生成的醌类代谢物能够直接损伤DNA并诱发基因组不稳定性；另一方面,通过代谢激活多环芳烃等前致癌物,形成DNA加合物,从而诱导致癌基因的突变并促进癌症的发生。CYP1B1基因多态性显著影响个体癌症易感性,并表现出种族及癌种间的异质性。此外,CYP1B1还通过药物(如紫杉烷类)代谢失活及调控AKT/ERK、FAK/SRC等信号通路介导化疗药物耐药,成为防治肿瘤耐药的重要靶点。其抑制剂的研究发现黄酮类、查尔酮类及二苯乙烯类等化合物通过竞争性结合或信号通路干预展现出逆转耐药的潜力。本文综述了CYP1B1在肿瘤代谢重编程、遗传易感性及治疗耐药性中的多维作用,并探讨了基于多组学整合与精准靶向策略的未来研究方向,为癌症的早期诊断、化学预防及联合治疗提供新思路。

Abstract:

Cytochrome P450 (CYP)1B1, as a key enzyme in extrahepatic metabolism, is characterized by tissue-specific high expression in various malignancies, while showing low or no expression in normal tissues. This enzyme promotes tumor occurrence and development through dual mechanisms: on one hand, it catalyzes the production of genotoxic 4-hydroxyestradiol, and the resulting oxidized quinone metabolites can directly damage DNA and induce genomic instability; on the other hand, it metabolically activates procarcinogens such as polycyclic aromatic hydrocarbons to form DNA adducts, which can induce mutations in oncogenes and promote cancer development. Polymorphisms in the CYP1B1 gene significantly affect individual cancer susceptibility and demonstrate heterogeneity across different races and cancer types. Furthermore, CYP1B1 mediates chemotherapy resistance through drug metabolism inactivation (such as paclitaxel) and regulation of signaling pathways including AKT/ERK and FAK/SRC, making it an important target for the prevention and treatment of tumor drug resistance. Research into its inhibitors has revealed that compounds such as flavonoids, chalcones, and stilbenes have potential to reverse drug resistance through competitive binding or signaling pathway intervention. This article reviews the multidimensional roles of CYP1B1 in tumor metabolic reprogramming, genetic susceptibility, and treatment resistance, while discussing future research directions based on multi-omics integration and precise targeting strategies, thus providing new insights for early cancer diagnosis, chemoprevention, and combination therapy