細胞色素P450之酵素調控及毒理意義   全文下載

Cytochrome P450: Enzyme Regulation and Toxicological Significance

藥物或環境化合物的藥效或毒性與其代謝有密切的關係。細胞色素P450（Cytochrome P450）酵素系統負責許多藥物、致癌物、食品添加物、環境污染物的氧化代謝反應。P450系統有龐多同功酵素，由此造成其廣泛受質特異性，目前P450依其氨基酸序列有統一的命名系統。微粒體P450酵素系統受不同生理及環境因子所調控，在調控過程表現出明顯的種族及組織特異性，此特性在危險評估及考量毒性標的器官時是重要考慮因素。P450酵素可受許多化學物質所誘導，典型誘導物包括苯巴比妥、3-甲基膽蔥及乙醇等。P450可受許多藥物、化合物、及天然物之純品或混合物所抑制。P450基因調控機轉有多樣性，在轉錄、轉譯階段都可被不同因素調控。P450的多型性在藥物代謝方面及疾病感受性具有重要意義。表現人類P450基因的細胞株對瞭解P450在藥物代謝或毒性會有重要貢獻。鈣離子進入細胞之機轉調控可能與P450有關連。傳統中藥對P450同功酵素可能產生誘導或抑制的作用。最後討論未來P450研究走向。

The pharmacological and toxicological responses of drugs and environmental chemicals are dependent upon metabolism of the compounds. Cytochrome P450 (P450)-dependent monooxygenases are the primary enzyme system responsible for the oxidative metabolism of drugs, carcinogens, food additives, and environmental chemicals. The underlying basis for the broad substrate specificity of P450 is that there are multiple forms of P450. A nomenclature system based on amino acid sequence homology is adopted for the increasing number of P450 hemoproteins. P450 genes are subject to regulation by many physiological and environmental factors. Regulation of P450 enzymes shows marked species and tissue specificity which plays an important role in species and tissue extrapolation of chemical risk assessment and target organ toxicity. P450 isoforms are readily inducible following exposure to foreign compounds of which phenobarbital, 3-methylcholanthrene, and ethanol are the prototypic inducing agents. Many drugs and natural compounds are potent inhibitors of P450 and dependent catalytic activity. Mechanism of P450 regulation also shows multiplicity at the transcriptional, translational, and post-translational stages. Polymorphism and racial difference are important determinants of drug metabolism and susceptibility to diseases in humans. Traditional Chinese medicines have the ability to induce and inhibit multiple forms of P450 monooxygenases. Expression of human P450 in mammalian cell lines provides an alternative system to study the functions of P450s in xenobiotic metabolism and toxicity in humans. P450 may be assoicated with regulation of cellular entry of calcium. Finally, the perspective of future P450 research is discussed.