細胞核接受體PXR (pregnane X receptor)參與在藥物代謝基因細胞色素P450 3A4 (簡稱CYP3A4) 和多重抗藥性基因MDR1轉錄作用的誘發機制。PXR可由不同化學結構的接受體配合基所活化；而在不同的動物種別中，PXR配合基的活化能力具有差異性。目前約有50%的臨床用藥事由CYP3A4所代謝。而CYP3A4的個體表現差異性頗大，是造成藥物反應不一及藥物交互作用的重要因素。根據研究顯示CYP3A4的個體表現差異性主要與基因多型性有關，但CYP3A4本身的突變發生率很小，不足以完全解釋眾多的個體差異性。學者Zhang等人曾證實PXR的變異型蛋白質對CYP3A4的誘發能力會有所改變，顯示PXR的基因多型性可能不僅影響CYP3A4的活性表現，也可能改變PXR與誘發劑結合的特異性(Pharmacogenetics. 2001; 11: 555-72)。因此我們以PCR-SSCP偵測方法對86位國人受試者進行篩檢，並進而發現四種基因點突變，其中二種造成胺基酸序列的改變，分別是V140M與Q158K。變異型V140M於2001年已由學者Hustert等人於高加索人種中所發現並進行研究(Drug Metab Dispos. 2001; 29: 1454-9)，而Q158K則是屬於新發現、中國人獨有的變異型。將變異型Q158K轉染至LS174T細胞中進行實驗可發現Q158K經由rifampin、nifedipine或paclitaxel等藥物活化後，對CYP3A4基因啟動區的誘發能力明顯較野生型低，但在clotrimazole、spironolactone或mifepristone等藥物的處理下，Q158K對CYP3A4基因啟動區的調控情形則與野生型雷同。依據西方點墨法可得知PXR野生型與變異型Q158K在LS174T細胞中的蛋白質表現量約略相等。此外，我們也由allele-specific PCR的分析方法確認Q158K的對偶基因發生率為0.0058。總合上述實驗結果顯示當投與不同的PXR配合基時，變異型Q158K可能會改變CYP3A4的活性，進而造成個體對藥物反應的差異性。

　　The pregnane X receptor (PXR, also known as steroid and xenobiotic receptor, SXR) is a nuclear receptor which is responsible for induction of CYP3A4 enzyme and MDR1 (P-glycoprotein) transporter. PXR is activated by ligands with different chemical structures. The PXR ligands varies among animal species. The human CYP3A4 is responsible for approximately 50% of administrated drug metabolism. However, CYP3A4 exhibits significant inter-individual variation which is a major basis for drug interaction. Clinical studies with CYP3A4 substrates suggest that 90% of the variability has been attributed to genetic factors. The low frequency of the CYP3A4 mutations indicates a limited role of CYP3A4 variants. Zhang et al. provided the evidence liking variant PXR proteins to altered CYP3A4 induction and drug clearance (Pharmacogenetics. 2001; 11: 555-72). Genetic polymorphism of PXR may not only affect the basal and induced activity of CYP3A4, it may also affect the specificity to the inducers. We screened a group of 86 Chinese subjects for PXR mutations by PCR-SSCP. Four SNPs were identified including 2 non-synonymous variants (V140M and Q158K). The V140M variant has been reported in Caucasians (Drug Metab Dispos. 2001; 29: 1454-9), while the Q158K is a novel SNP in Chinese. Expressed in LS174T cells, the Q158K variant exhibited a decreased transactivation of CYP3A4 promoter reporter gene in response to rifampin, nifedipine, and paclitaxel. But it stimulated transcription of reporter gene nearly as efficiently as wild-type PXR following the clotrimazole, spironolactone, or mifepristone treatment. Western blot analysis showed that the plasmid encoding the variant Q158K directed the expression of similar amount of protein compared with wild-type. The allelic frequency of Q158K is 0.0058 by allele-specific PCR detection. These data suggest that the subjects with Q158K variant may cause idiosyncracy when different PXR ligands prescribed.

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