China-UK Low Carbon College, Shanghai Jiaotong University, Shanghai, China.
School of Environmental Science and Engineering, Shanghai Jiaotong University, Shanghai, China.
Curr Cancer Drug Targets. 2021;21(1):21-54. doi: 10.2174/1568009620666201006143419.
CYP1A1 and CYP1B1 are extrahepatic P450 family members involved in the metabolism of procarcinogens, such as PAHs, heterocyclic amines and halogen-containing organic compounds. CYP1A1/1B1 also participate in the metabolism of endogenous 17-β-estradiol, producing estradiol hydroquinones, which are the intermediates of carcinogenic semiquinones and quinones. CYP1A1 and CYP1B1 proteins share approximately half amino acid sequence identity but differ in crystal structures. As a result, CYP1A1 and CYP1B1 have different substrate specificity to chemical procarcinogens. This review will introduce the general molecular biology knowledge of CYP1A1/1B1 and the metabolic processes of procarcinogens regulated by these two enzymes. Over the last four decades, a variety of natural products and synthetic compounds which interact with CYP1A1/1B1 have been identified as effective chemo-preventive agents against chemical carcinogenesis. These compounds are mainly classified as indirect or direct CYP1A1/1B1 inhibitors based on their distinct mechanisms. Indirect CYP1A1/1B1 inhibitors generally impede the transcription and translation of CYP1A1/1B1 genes or interfere with the translocation of aryl hydrocarbon receptor (AHR) from the cytosolic domain to the nucleus. On the other hand, direct inhibitors inhibit the catalytic activities of CYP1A1/1B1. Based on the structural features, the indirect inhibitors can be categorized into the following groups: flavonoids, alkaloids and synthetic aromatics, whereas the direct inhibitors can be categorized into flavonoids, coumarins, stilbenes, sulfur containing isothiocyanates and synthetic aromatics. This review will summarize the in vitro and in vivo activities of these chemo-preventive agents, their working mechanisms, and related SARs. This will provide a better understanding of the molecular mechanism of CYP1 mediated carcinogenesis and will also give great implications for the discovery of novel chemo-preventive agents in the near future.
CYP1A1 和 CYP1B1 是细胞色素 P450 家族的肝外成员，参与前致癌物如多环芳烃、杂环胺和含卤素有机化合物的代谢。CYP1A1/1B1 还参与内源性 17-β-雌二醇的代谢，生成雌二醇氢醌，这是致癌半醌和醌的中间产物。CYP1A1 和 CYP1B1 蛋白大约有一半的氨基酸序列相同，但晶体结构不同。因此，CYP1A1 和 CYP1B1 对化学前致癌物具有不同的底物特异性。这篇综述将介绍 CYP1A1/1B1 的一般分子生物学知识以及这两种酶调节的前致癌物的代谢过程。在过去的四十年里，已经鉴定出了许多与 CYP1A1/1B1 相互作用的天然产物和合成化合物，它们是对抗化学致癌作用的有效化学预防剂。这些化合物主要根据其不同的机制分为间接或直接 CYP1A1/1B1 抑制剂。间接 CYP1A1/1B1 抑制剂通常会阻碍 CYP1A1/1B1 基因的转录和翻译，或干扰芳香烃受体 (AHR) 从细胞质域到核内的易位。另一方面，直接抑制剂抑制 CYP1A1/1B1 的催化活性。根据结构特征，间接抑制剂可分为以下几类：黄酮类、生物碱类和合成芳烃，而直接抑制剂可分为黄酮类、香豆素类、二苯乙烯类、含硫异硫氰酸酯类和合成芳烃类。本综述将总结这些化学预防剂的体外和体内活性、作用机制及相关 SARs。这将为 CYP1 介导的致癌作用的分子机制提供更好的理解，也将对未来发现新型化学预防剂产生重要影响。
