Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz
Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz
复制标题
DOI：
10.1097/01.fpc.0000189797.03845.90
复制
发表时间：
2006-03
影响因子：
2.6
通讯作者：
Jue Wang;A. Sönnerborg;A. Rane;F. Josephson;S. Lundgren;L. Ståhle;M. Ingelman-Sundberg
中科院分区：
文献类型：
--
作者：
Jue Wang;A. Sönnerborg;A. Rane;F. Josephson;S. Lundgren;L. Ståhle;M. Ingelman-Sundberg
非核苷类逆转录酶抑制剂依非韦伦主要通过多态性细胞色素P450酶CYP2B6代谢。通过直接测序对 51 名接受依非韦伦治疗且血浆浓度高得惊人的患者中的 4 名受试者的基因组 DNA 进行了 CYP2B6 基因突变的直接测序筛查。鉴定出 4 个外显子单核苷酸多态性 (SNP)：516G>T、714G>A、785A>G 和 983T>C，以及 8 个内含子 SNP。单倍型分析显示 983T>C 与 785A>G 相关，定义了一个新的等位基因 CYP2B6*16。该等位基因总共存在于五名患者中。 CYP2B6.16 cDNA 在酵母和 HEK293 细胞中表达，并且在两个异源系统中与野生型 cDNA 相比，形成的蛋白质显着减少。相比之下，使用安非他酮作为探针底物，酶变体的催化活性与 CYP2B6.1 酶没有不同。 CYP2B6*16 等位基因在瑞典人中未发现，在土耳其人中以 4% 的频率出现，但在非洲人中很常见。与其他患者相比，五名 CYP2B6*16 携带者（非洲裔）的稳态依非韦伦水平显着较高。 516G>T 携带者（CYP2B6*6 和 CYP2B6*9）中也观察到较高的依法韦仑浓度。总之，鉴定出一种新的 CYP2B6*16 等位基因，该等位基因会导致相应酶的表达减少，并发现该等位基因会影响依非韦伦的体内代谢，这一发现对黑人群体的抗 HIV 治疗具有潜在影响。
The non-nucleoside reverse transcriptase inhibitor efavirenz is mainly metabolised by the polymorphic cytochrome P450 enzyme CYP2B6. Genomic DNA from four subjects in a group of 51 patients being treated with efavirenz and having surprisingly high plasma concentrations were screened by direct sequencing for mutations in the CYP2B6 gene. Four exonic single nucleotide polymorphisms (SNPs), 516G>T, 714G>A, 785A>G and 983T>C, and eight intronic SNPs were identified. Haplotype analysis revealed that 983T>C was linked with 785A>G defining a novel allele, CYP2B6*16. This allele was present in totally five of the patients. The CYP2B6.16 cDNA was expressed in yeast and HEK293 cells and significantly less protein was formed compared to the wild-type cDNA, in both heterologous systems. By contrast, the catalytic activity of the enzyme variant was not different from the CYP2B6.1 enzyme, using bupropion as a probe substrate. The CYP2B6*16 allele was not found in Swedes, was present at 4% frequency among Turks, but was common among Africans. The steady-state level of efavirenz was significantly higher in the five carriers of CYP2B6*16, being of African origin, compared to the other patients. Higher efavirenz concentrations were also seen in carriers of 516G>T (CYP2B6*6 and CYP2B6*9). In conclusion, a novel CYP2B6*16 allele causing less expression of the corresponding enzyme was identified and found to influence the metabolism of efavirenz in vivo, a finding that is of potential impact for anti-HIV therapy in black populations.