Institute of Digestive Disease, Southwest Hospital, The Third Military Medical University, Chongqing 400038, PR China.
Mol Med Rep. 2012 Jul;6(1):75-82. doi: 10.3892/mmr.2012.900. Epub 2012 May 3.
The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n = 118) and without (non-DILI) (n = 155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 *1a, *1b, *5 and *15, with their respective frequencies being 23.44, 66.30, 0.73 and 9.52% in a total of 273 individuals. The logistic regression analysis indicated that the *15 haplotype was associated with susceptibility to DILI (p = 0.03, OR = 2.04, 95% CI 1.05-3.96). The frequency of the *15 haplotype in DILI patients was significantly higher than that in non-DILI patients (p = 0.03). In the subgroup analysis, the *15 haplotype was associated with susceptibility to cholestatic/mixed injury (p = 0.03, OR = 2.31, 95% CI 1.06-5.02). Functional assessment of the OATP1B1 *15 haplotype revealed that the activity of bile acid uptake was markedly reduced compared to the three other haplotypes. In the inhibition study, the inhibition by rifampin in the *15 haplotype was greater compared to that in the other haplotypes. These results suggest that the OATP1B1 *15 haplotype is an important predisposing factor for rifampin-induced liver injury.
有机阴离子转运多肽 1B1（OATP1B1，由 SLCO1B1 编码）在运输内源性和外源性化合物（如胆汁酸和利福平）方面发挥着重要作用。在这项研究中，通过整合群体遗传分析和功能研究，研究了 OATP1B1 多态性与利福平肝毒性的关系。共招募了 273 名接受利福平治疗的无相关性患者。在药物（利福平）诱导的肝损伤（DILI）患者（n = 118）和无肝损伤（非-DILI）患者（n = 155）中检测了等位基因频率。进行功能分析以确定利福平对胆汁酸的抑制是否与 OATP1B1 变体有关。在本研究中，在中国人群中检测到 OATP1B1 中的 24 个单核苷酸多态性（SNP），其中两个导致氨基酸变化（rs2306283 和 rs4149056）。由这两个 SNP 构建的单倍型为 OATP1B11a、1b、5 和15，它们在总共 273 个人中的频率分别为 23.44%、66.30%、0.73%和 9.52%。逻辑回归分析表明，15 单倍型与 DILI 易感性相关（p = 0.03，OR = 2.04，95%CI 1.05-3.96）。DILI 患者15 单倍型的频率明显高于非 DILI 患者（p = 0.03）。在亚组分析中，15 单倍型与胆汁淤积/混合损伤的易感性相关（p = 0.03，OR = 2.31，95%CI 1.06-5.02）。对 OATP1B115 单倍型的功能评估表明，与其他三种单倍型相比，胆汁酸摄取的活性明显降低。在抑制研究中，与其他单倍型相比，利福平对15 单倍型的抑制作用更大。这些结果表明，OATP1B115 单倍型是利福平诱导肝损伤的重要易感因素。
