Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U, Roots I
Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University Berlin.
Clin Pharmacol Ther. 2001 Mar;69(3):169-74. doi: 10.1067/mcp.2001.114164.
P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin.
We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers.
In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism.
Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein.
This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.
P-糖蛋白是多药耐药基因1（MDR1）的基因产物，它赋予肿瘤细胞对多种抗肿瘤药物的耐药性，但在药物治疗中普通药物的生物利用度方面也起着重要作用。最近发现了MDR1基因的多种多态性。外显子26中的一个沉默突变（C3435T）与肠道P-糖蛋白表达及地高辛的口服生物利用度相关。
我们希望建立针对主要已知MDR1单核苷酸多态性的简便且经济高效的基因分型检测方法，并在大量志愿者样本中研究这些单核苷酸多态性的等位基因频率分布。
在本研究中，使用聚合酶链反应和限制性片段长度多态性方法，对461名白人志愿者中主要MDR1等位基因的分布进行了测定。
发现了5种氨基酸替换，其中Asn21Asp的等位基因频率为11.2%，Ser400Asn的等位基因频率为5.5%。令人惊讶的是，在外显子21的同一位置发现了3种变体：2677G（56.4%）、2677T（41.6%）和2677A（1.9%），分别编码893Ala、Ser或Thr。在2例（0.2%）中发现了一种新的错义突变Gln1107Pro。内含子和沉默多态性的频率最高；C3435T在53.9%的受试者中杂合出现，28.6%的个体为3435T/T纯合携带者，其P-糖蛋白功能受到抑制。
本研究首次对大量白人受试者样本中的MDR1变异基因型分布进行了分析。它为大规模临床研究MDR1等位基因变异对大量药物生物利用度的功能作用提供了依据。
