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Cytochrome P450s and molecular epidemiology

机译：细胞色素P450与分子流行病学

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Abstract: Cytochrome P450 (P450) represent a superfamily of heme-containing monooxygenases that are found throughout the animal and plant kingdoms and in many microorganisms. A number of these enzymes are involved in biosynthetic pathways of steroid synthesis but in mammals the vast majority of P450s function to metabolize foreign chemicals or xenobiotics. In the classical phase I reactions on the latter, a membrane-bound P450 will hydroxylate a compound, usually hydrophobic in nature, and the hydroxyl group will serve as a substrate for the various transferases or phase II enzymes that attach hydrophilic substituents such as glutathione, sulfate or glucuronic acid. Some chemicals, however, are metabolically-activated by P450s to electrophiles capable of reacting with cellular macromolecules. The cellular concentrations of the chemical and P450, reactivity of the active metabolite with nucleic acid and the repairability of the resultant adducts, in addition to the nature of the cell type, likely determines whether a chemical will be toxic and kill the cell or will transform the cell. Immunocorrelative and cDNA-directed expression have been used to define the substrate specificities of numerous human P450s. Levels of expression of different human P450 forms have been measured by both in vivo and in vitro methodologies leading to the realization that a large degree of interindividual differences occur in P450 expression. Reliable procedures for measuring P450 expression in healthy and diseased subjects will lead to prospective and case-cohort studies to determine whether interindividual differences in levels of P450 are associated with susceptibility or resistance to environmentally-based disease.!28
机译：摘要：细胞色素P450（P450）代表了一个含血红素的单加氧酶的超家族，遍布整个动植物界以及许多微生物中。这些酶中的许多酶都参与类固醇合成的生物合成途径，但在哺乳动物中，绝大多数P450发挥功能来代谢外来化学物质或异种生物。在后者的经典I相反应中，与膜结合的P450会羟基化通常为疏水性的化合物，并且羟基将充当各种连接了亲水性取代基（如谷胱甘肽）的转移酶或II相酶的底物，硫酸或葡萄糖醛酸。但是，某些化学物质会被P450代谢活化为能够与细胞大分子反应的亲电子试剂。化学物质和P450的细胞浓度，活性代谢产物与核酸的反应性以及所得加合物的可修复性，除了细胞类型的性质外，还可能决定化学物质是否会毒性并杀死细胞或转化细胞。免疫相关性和cDNA指导的表达已用于定义许多人P450的底物特异性。已经通过体内和体外方法测量了不同人P450形式的表达水平，从而认识到在P450表达中存在很大程度的个体差异。在健康和患病受试者中测量P450表达的可靠方法将导致前瞻性研究和案例研究，以确定P450水平的个体差异是否与对环境性疾病的易感性或耐药性相关！28

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