俄亥俄州立大学的一项最新研究表明,人类肝脏细胞中的一个微小基因变异在未来或能用于指示患者所需药物剂量的高低,而且这几乎对市场上一半左右的临床药物适用。
科学家所识别的这个变异改变了肝脏中蛋白的表达水平,该蛋白能够对药物产生应答。实验表明,这个变异使得大约45%到60%的药物给药剂量产生了变化,而这些药物的疾病治疗范围也是十分的广泛。
在同源染色体上同一位置,存在着不同形态的基因,即等位基因。在本课题中,研究人员发现,其中一个等位基因的活性或表达水平与它的同伴基因是有差异的。这个微小的差异即为单核苷酸多肽(SNP)。研究人员表示,该SNP影响了基因的蛋白生成,从而降低了酶CYP3A4的水平。
一般来说,肝脏中药物代谢地越快,组织和机体中就能更快地生成这种酶。当酶CYP3A4的水平由于该SNP的存在而降低时,人就很有可能只需要很小的药物剂量就可以达到疗效。但是同样的,对于含有这种变异的人来说,如果相同药物的剂量越高,可能就更易对人体产生危害。
进一步研究证实,在对一类降低胆固醇含量的药物的试验中,相比于没有该SNP的人,含有这种变异的人确实只需要更低剂量的药物就能达到同样的效果。
研究人员表示,这个变异能够为医生的临床实践提供一种分子标记,用于调整很多药物的给药剂量,尤其是抗癌药物。
目前市场上一些抗癌药物的治疗指标非常狭窄,也就是说如果医生给患者使用一个稍微高的剂量,就可能导致毒性反应。我们相信该生物标记分子也能够用于预测毒性阈值,这对癌症患者是十分有益的。这项研究的负责人Danxin Wang教授介绍说。
这项研究结果发布在The Pharmacogenomics Journal杂志的在线版本上。(生物谷Bioon.com)
Hepatology:发现Cdc42在肝脏再生过程中调控的新机制
Gastroenterology:发现重要肝脏免疫调控蛋白LSECtin
MCP:2型糖尿病发病过程中肝脏线粒体蛋白质组及其修饰的动态变化
生物谷推荐原文出处:
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.