Sakaeda Toshiyuki, Nakamura Tsutomu, Okumura Katsuhiko
Department of Hospital Pharmacy, School of Medicine, Kobe University.
Biol Pharm Bull. 2002 Nov;25(11):1391-400. doi: 10.1248/bpb.25.1391.
The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.
多药耐药转运蛋白MDR1/P-糖蛋白是MDR1基因的产物，是一种170 kDa的糖基化膜蛋白，属于膜转运蛋白的ATP结合盒超家族。MDR1作为一种能量依赖性外排泵，将其底物输出细胞。MDR1最初是从耐药肿瘤细胞中分离出来的，是多药耐药机制的一部分，但在过去十年中，已阐明人类MDR1也在全身表达，通过输出不必要的或有毒的外源性物质或代谢产物，赋予组织内在耐药性。许多结构不相关的药物是MDR1的底物，MDR1和其他转运蛋白被认为是调节药代动力学和药效学的一类重要蛋白质。2000年，霍夫迈尔等人对MDR1多态性进行了系统筛查，检测到15个单核苷酸多态性（SNP）。他们还指出，外显子26中第3435位的多态性（C3435T），一种沉默突变，影响十二指肠中MDR1蛋白的表达水平，从而影响地高辛的肠道吸收。迄今为止，已使用更大的群体广泛研究了C3435T的基因型频率，并阐明了种族间差异，在MDR1基因的27个位置共发现了28个SNP。世界各地也开展了关于MDR1基因型相关的MDR1表达和药代动力学的临床研究；然而，结果并不总是与霍夫迈尔的报告一致。在本综述中，对已发表的报告进行了总结，以便未来基于MDR1基因分型实现药物治疗的个体化。此外，最近的研究提出了MDR1和相关转运蛋白在调节细胞凋亡和免疫方面发挥重要作用的可能性，事实上，有报告称MDR1与炎症性肠病、HIV感染和肾细胞癌的易感性有关。在此，对这些问题也进行了总结，并简要介绍了其他转运蛋白药物基因组学领域的知识现状。
