亚洲人群中MDR1和CYP3A4基因的遗传多态性以及MDR1单倍型对心脏移植受者环孢素处置的影响。

Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients.

作者信息

Chowbay Balram, Cumaraswamy Sivathasan, Cheung Yin Bun, Zhou Qingyu, Lee Edmund J D

机构信息

Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Republic of Singapore.

出版信息

Pharmacogenetics. 2003 Feb;13(2):89-95. doi: 10.1097/00008571-200302000-00005.

DOI:10.1097/00008571-200302000-00005

PMID:12563178

Abstract

Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients.

摘要

肠道细胞色素P450 3A4（CYP3A4）和P-糖蛋白（P-gp）在口服环孢素（CsA）的代谢中均起着至关重要的作用。我们研究了CYP3A4（启动子区域以及外显子5、7和9）和MDR1（外显子12、21和26）基因的遗传多态性，以及这些多态性对稳定期心脏移植患者（n = 14）口服CsA药代动力学的影响。CYP3A4多态性在亚洲人群和移植患者中较为罕见。单倍型分析显示，中国人中有12种单倍型，马来西亚人中有8种，印度人中有10种。T-T-T是所有种族中最常见的单倍型。在所有三个位点的纯合突变基因型（TT-TT-TT）频率在印度人中最高（31%），而中国人和马来西亚人分别为19%和15%。在心脏移植患者中，与具有C-G-C单倍型的患者相比，具有T-T-T单倍型的患者的CsA暴露量（AUC(0 - 4 h)、AUC(0 - 12 h)和C(max)）较高。这些发现表明，单倍型而非基因型影响移植患者体内CsA的处置。