文章：

细胞色素P450酶在内源性信号通路和环境癌变中的作用

The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis

原文发布日期：2006-12-01

DOI: 10.1038/nrc2015

类型: Review Article

开放获取: 否

要点：

1. The metabolism of xenobiotics by xenobiotic-metabolizing enzymes (XMEs) has been classified into phase I (functionalization) and phase II (conjugation) reactions. Cytochrome P450 (CYP) enzymes comprise 70–80% of all phase I XMEs.
2. Although originally thought to be responsible for drug metabolism almost exclusively in the liver, it has now been realized that all XMEs participate in many crucial endogenous functions, probably in every eukaryotic cell and many prokaryotes.
3. Of the 57 human CYP genes in 18 families, the members of the CYP1 to CYP4 families oxygenate thousands of xenobiotics (and endogenous substrates), whereas all members of the CYP5 family and higher principally metabolize endogenous substrates in a highly substrate-specific manner.
4. CYP enzymes can cause tumour initiation through the formation of reactive intermediates (from exogenous and endogenous substrates). CYPs also participate in tumour initiation and progression through inflammation, other eicosanoid-mediated processes and other signal-transduction pathways.
5. There is an interesting 'xenosensor' relationship that is not yet well understood among CYPs, XME receptors that regulate CYP expression and xenobiotic-related transporters (XRTs).
6. Although several high-penetrance, predominantly monogenic (hPpM), traits including cancer have been correlated with various human CYP genes, the identification of a specific procarcinogen is rarely possible.
7. Pharmacokinetic studies of several environmental toxicants in Cyp1 knockout mouse lines have shown that CYP1A1, CYP1A2 and CYP1B1 might be beneficial or detrimental — depending on their time-specific, organ-specific, tissue-specific and cell-type-specific expression. These new findings suggest that animal studies and human epidemiological studies might need to be revisited.
8. Whereas oral drugs more commonly use the portal vein system (and first-pass elimination kinetics), we suggest that the lymphatic system might be more important in delivering the very hydrophobic oral polycyclic aromatic hydrocarbons (PAHs) and polyhalogenated aromatic hydrocarbons (PHAHs) to target tissues. This is especially relevant to clinical medicine, because oral exposure to these procarcinogens is the most predominant route. More focus on pharmacokinetic and pharmacodynamic studies of hydrophobic procarcinogens in animal models (and extrapolation to humans) is needed.
9. A two-tiered model is proposed for the risk of developing cancer as a result of the environment. First, human inter-individual differences in the up-front hPpM traits, encoded by phase I genes, should have profound effects on a small (5–15%) proportion of any population who have no significant polymorphisms in downstream target genes. Second, all downstream targets of phase-I-mediated reactive intermediates can have their own important polymorphisms, always resulting in a unimodal gradient response.

要点翻译：

1. 外源性物质通过外源性物质代谢酶（XMEs）的代谢可分为Ⅰ相（功能化）和Ⅱ相（结合）反应。细胞色素P450（CYP）酶占所有Ⅰ相XMEs的70%-80%。
2. 尽管最初认为这些酶几乎仅负责肝脏中的药物代谢，但现在已认识到所有XMEs都参与许多关键的内源性功能，可能存在于每个真核细胞和许多原核生物中。
3. 在18个家族的57个人类CYP基因中，CYP1至CYP4家族的成员为数千种外源性物质（及内源性底物）加氧，而CYP5家族及更高级家族的所有成员主要以高度底物特异性的方式代谢内源性底物。
4. CYP酶可通过形成反应性中间体（来自外源性和内源性底物）引发肿瘤。CYP还通过炎症、其他类二十烷酸介导的过程及其他信号转导途径参与肿瘤的发生和进展。
5. 在CYP、调控CYP表达的XME受体以及外源性物质相关转运蛋白（XRTs）之间存在一种有趣的“外源传感器”关系，目前尚未被充分理解。
6. 尽管包括癌症在内的几种高外显率、主要为单基因（hPpM）性状与多个人类CYP基因相关，但很少能鉴定出特定的前致癌物。
7. 对Cyp1基因敲除小鼠系中几种环境毒物的药代动力学研究表明，CYP1A1、CYP1A2和CYP1B1可能有益或有害——这取决于它们的时间特异性、器官特异性、组织特异性和细胞类型特异性表达。这些新发现提示，可能需要重新审视动物研究和人类流行病学研究。
8. 虽然口服药物更常使用门静脉系统（及首过消除动力学），但我们认为淋巴系统在将高度疏水性的口服多环芳烃（PAHs）和多卤代芳烃（PHAHs）递送至靶组织方面可能更为重要。这与临床医学尤其相关，因为口服这些前致癌物是最主要的暴露途径。需要更关注疏水性前致癌物在动物模型中的药代动力学和药效学研究（及向人类的推衍）。
9. 针对环境所致癌症风险提出了一个双层模型。首先，由Ⅰ相基因编码的前端hPpM性状的人类个体间差异，应对小部分（5%-15%）在下游靶基因中无显著多态性的群体产生深远影响。其次，所有Ⅰ相介导的反应性中间体的下游靶点都可能存在自身重要的多态性，总是导致单峰梯度反应。

英文摘要：

Some cytochrome P450 (CYP) heme-thiolate enzymes participate in the detoxication and, paradoxically, the formation of reactive intermediates of thousands of chemicals that can damage DNA, as well as lipids and proteins. CYP expression can also affect the production of molecules derived from arachidonic acid, and alters various downstream signal-transduction pathways. Such changes can be precursors to malignancy. Recent studies in mice have changed our perceptions about the function of CYP1 enzymes. We suggest a two-tiered system to predict an overall inter-individual risk of tumorigenesis based on DNA variants in certain 'early defence' CYP genes, combined with polymorphisms in various downstream target genes.

摘要翻译： 

某些细胞色素P450（CYP）血红素-硫醇盐酶参与数千种化学物质的解毒过程，但矛盾的是，它们也能形成可损伤DNA、脂质和蛋白质的活性中间产物。CYP的表达还可影响由花生四烯酸衍生分子的生成，并改变多种下游信号转导通路。这些变化可能成为恶性肿瘤的前驱。近期小鼠研究改变了我们对CYP1酶功能的认识。我们提出一个双层系统，通过结合某些“早期防御”CYP基因的DNA变异与多种下游靶基因的多态性，来预测个体间总体肿瘤发生风险。

原文链接：

The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis