Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, BC, Canada.
Sci Rep. 2019 Feb 18;9(1):2217. doi: 10.1038/s41598-018-38452-z.
A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.
包括异烟肼、利福平、乙胺丁醇和吡嗪酰胺在内的多种药物联合治疗已被证明是绝大多数结核病 (TB) 患者的有效选择。然而，各种药物不良反应 (ADR) 限制了其优点，抗结核药物性肝毒性 (ATDH) 是一种常见且有时严重的 ADR。本研究旨在探讨中国人群中两个核受体基因——孕烷 X 受体 (PXR) 和组成型雄烷受体 (CAR)——的多态性与 ATDH 风险之间的关系。招募了在抗结核治疗过程中出现或未出现肝毒性的患者。从外周血中提取 DNA，并使用改良多重连接检测反应技术确定所选单核苷酸多态性 (SNP) 的基因型。采用加性、显性和隐性三种遗传模型以及单体型、SNP-SNP 相互作用分析来评估 ATDH 的遗传风险。共纳入 502 例患者 (203 例 ATDH 和 299 例非 ATDH)。结果表明，PXR 中的 rs7643645 次要等位基因和 H0010001 单体型与 ATDH 风险降低相关，提示由 PXR 调节的药物代谢酶参与了 ATDH 的发病机制。需要更多的研究来验证这一结果。
