俄亥俄州立大學(xué)的一項(xiàng)最新研究表明,，人類肝臟細(xì)胞中的一個(gè)微小基因變異在未來(lái)或能用于指示患者所需藥物劑量的高低,，而且這幾乎對(duì)市場(chǎng)上一半左右的臨床藥物適用,。
科學(xué)家所識(shí)別的這個(gè)變異改變了肝臟中蛋白的表達(dá)水平,，該蛋白能夠?qū)λ幬锂a(chǎn)生應(yīng)答,。實(shí)驗(yàn)表明,，這個(gè)變異使得大約45%到60%的藥物給藥劑量產(chǎn)生了變化,，而這些藥物的疾病治療范圍也是十分的廣泛,。
在同源染色體上同一位置，存在著不同形態(tài)的基因,，即等位基因,。在本課題中，研究人員發(fā)現(xiàn),，其中一個(gè)等位基因的活性或表達(dá)水平與它的同伴基因是有差異的,。這個(gè)微小的差異即為單核苷酸多肽（SNP）。研究人員表示,，該SNP影響了基因的蛋白生成,，從而降低了酶CYP3A4的水平。
一般來(lái)說(shuō),，肝臟中藥物代謝地越快,，組織和機(jī)體中就能更快地生成這種酶。當(dāng)酶CYP3A4的水平由于該SNP的存在而降低時(shí),，人就很有可能只需要很小的藥物劑量就可以達(dá)到療效,。但是同樣的，對(duì)于含有這種變異的人來(lái)說(shuō),，如果相同藥物的劑量越高,，可能就更易對(duì)人體產(chǎn)生危害。
進(jìn)一步研究證實(shí),，在對(duì)一類降低膽固醇含量的藥物的試驗(yàn)中,，相比于沒有該SNP的人，含有這種變異的人確實(shí)只需要更低劑量的藥物就能達(dá)到同樣的效果,。
研究人員表示,，這個(gè)變異能夠?yàn)獒t(yī)生的臨床實(shí)踐提供一種分子標(biāo)記，用于調(diào)整很多藥物的給藥劑量,，尤其是抗癌藥物,。
目前市場(chǎng)上一些抗癌藥物的治療指標(biāo)非常狹窄，也就是說(shuō)如果醫(yī)生給患者使用一個(gè)稍微高的劑量,，就可能導(dǎo)致毒性反應(yīng),。我們相信該生物標(biāo)記分子也能夠用于預(yù)測(cè)毒性閾值，這對(duì)癌癥患者是十分有益的,。這項(xiàng)研究的負(fù)責(zé)人Danxin Wang教授介紹說(shuō),。
這項(xiàng)研究結(jié)果發(fā)布在The Pharmacogenomics Journal雜志的在線版本上,。（生物谷Bioon.com）
Hepatology：發(fā)現(xiàn)Cdc42在肝臟再生過(guò)程中調(diào)控的新機(jī)制
Gastroenterology：發(fā)現(xiàn)重要肝臟免疫調(diào)控蛋白LSECtin
MCP：2型糖尿病發(fā)病過(guò)程中肝臟線粒體蛋白質(zhì)組及其修飾的動(dòng)態(tài)變化
生物谷推薦原文出處：
The Pharmacogenomics Journal doi: 10.1038/tpj.2010.28
Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs
D Wang1, Y Guo2, S A Wrighton2, G E Cooke3 and W Sadee1
1Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, Ohio State University, Columbus, OH, USA
2Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
3Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH, USA
Cytochrome P450 3A4 (CYP3A4) metabolizes ~50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6–6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2–0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.
