PXR-ALAS1: A key regulatory pathway in liver toxicity induced by isoniazid-rifampicin antituberculosis treatment

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-dependent transcription factor, and rifampicin is a human PXR-specific activator. Rifampicin and isoniazid co-therapy targets porphyrin biosynthesis via PXR and results in hepatic protoporphyrin IX accumulation and subsequent liver injury. The present study aimed to investigate the associations between genetic polymorphisms in NR1I2 and ATDH in an Eastern Chinese Han population.A 1:4 matched case-control study was conducted using 146 ATDH cases and 584 controls. Seven single nucleotide polymorphisms (SNPs) were detected and analysed. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking history and drinking history as covariates.Patients carrying the GG genotype of rs7643645 were at a higher risk of ATDH than those carrying the AA genotype (OR = 1.864, 95% CI: 1.106–3.141, P = .020), and significant differences were also found under the recessive model (P = .029) and additive model (P = .021). Patients with a polymorphism at rs2276707 were at a reduced risk of ATDH under the recessive model (OR = 0.600, 95% CI: 0.364–0.988, P = .045). Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the additive model (rs7643645, OR = 1.429, 95% CI: 1.027–1.988, P = .034) and recessive model (rs2276707, OR = 0.478, 95% CI: 0.253–0.902, P = .023). Functional annotation using ENCODE data also indicated that rs2276707 and rs7643645 were located in the histone modification regions targeting enhancers or promoter (H3K4Me1, H3K4Me3 and H3K27Ac).Based on this case-control study, SNPs rs7643645 and rs2276707 in NR1I2 may contribute to susceptibility to ATDH in Eastern Chinese Han anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.