Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Wang, Yu; Xiang, Xi; Huang, Weiwei; Sandford, Andrew J.; Wu, Shouquan; Zhang, Miaomiao; Wang, Minggui; Chen, Guo; He, Jian-Qing

doi:10.1038/s41598-018-38452-z

Cited by 24 publications

(34 citation statements)

References 52 publications

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“…These two hypothesized protective mechanisms are consistent with our results. In another study of the Chinese population, rs7643645 but not rs3814055 in PXR showed a statistically significant association[14]. This was somewhat different from our results.…”

Section: Discussioncontrasting

confidence: 99%

“…Overall, genetic polymorphisms of PXR may be associated with the risk of ATDILI resulting from rifampicin and isoniazid anti-tuberculosis co-therapy. Some PXR variants have been shown to increase susceptibility to ATDILI in an Indonesian population and a Chinese population, although the results were inconsistent and require further verification[14–16].…”

Section: Introductionmentioning

confidence: 99%

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Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury

et al. 2019

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Background Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI). Materials and methods A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. Results The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42–0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06–3.43, p = 0.028 and OR 1.81; 1.06–3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs. Conclusion Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury

et al. 2019

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“…for example, a single-nucleotide polymorphism (SNP) in PXR decreases risk for anti-tuberculosis druginduced hepatotoxicity [39].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

Little

Dutta

et al. 2020

Preprint

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Background: Pharmacological activation of the host xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding the physiological functions of PXR and CAR on the gut microbiome, which is an important regulator for the host immune surveillance and bile acid (BA) metabolism. We examined the gut microbiome composition and BA metabolites in high vs. low PXR/CAR-expressing mice, and in mice that are deficient in PXR, CAR, or both, at two developmental ages. We also utilized humanized PXR transgenic (hPXR-TG) mice to compare the species-specific effect of PXR on the gut microbiome. Results: We discovered bivalent hormetic functions of PXR and CAR in modulating the richness of the gut microbiome and inflammatory biomarkers: the high PXR/CAR expressers had higher microbial richness, pro-inflammatory bacteria (distinct taxa in Helicobacteraceae and Helicobacter), and fecal pro-inflammatory cytokines, suggesting higher immune surveillance to prevent the colonization of harmful bacteria. Interestingly, the absence of PXR or CAR also increased the microbial richness, and absence of both receptors synergistically increased the microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria (Helicobacteraceae and Helicobacter). Most notably, deficiency in both PXR and CAR markedly increased the relative abundance of Lactobacillus, which is capable of bile salt hydrolase (BSH) activity. This corresponded to a decrease in major primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice, including a higher representation of Prevotella. hPXR-TG mice also had higher 12-OH BAs but lower 6-OH BAs, suggesting PXR’s species-specific role in modulating host hepatic BA synthesis. Conclusions: This study is the first to show that the host PXR and CAR profoundly influence the composition of the gut microbiome and its BA metabolites, with a bivalent hormetic relationship between PXR/CAR levels and microbial richness, unveiling the involvement of PXR/CAR-microbiome interactions in host immune surveillance and BA metabolism.

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“…19 To date, a number of studies have been conducted to investigate the potential association between NR1I2 genetic polymorphisms and the risk of ATDH, with inconsistent results being obtained. [20][21][22][23][24] For example, earlier studies from Indonesia showed that patients with the TT genotype at rs3814055 had a significantly increased risk of ATDH, 21 but another study from China reached the opposite conclusion, namely, the T allele of rs3814055 was associated with a decreased risk for ATDH. 20 However, a systematic review and meta-analysis can be used to pool results from different studies, thereby enhancing the precision of estimates of treatment effects.…”

Section: Introductionmentioning

confidence: 99%

NR1I2 genetic polymorphisms and the risk of anti‐tuberculosis drug‐induced hepatotoxicity: A systematic review and meta‐analysis

Yang

Qiu

Jin

et al. 2020

Pharmacology Res & Perspec

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Anti‐tuberculosis drug‐induced hepatotoxicity (ATDH) is a serious adverse drug reaction. Conflicting results have been obtained regarding the associations of nuclear receptor subfamily 1 group I member 2 (NR1I2) gene polymorphisms on susceptibility to ATDH. Therefore, we aimed to evaluate the associations using a systematic review/meta‐analysis approach. PubMed, Medline, Cochrane Library, Web of Science and SinoMed databases were searched for all eligible studies from inception to June 10, 2020. Pooled adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were employed to evaluate the strength of the association between the NR1I2 polymorphisms and the risk of ATDH. Subgroup analysis was performed by region of origin, and meta‐regression were performed to detect potential sources of heterogeneity. A total of five case‐control studies involving 572 cases and 1867 controls were identified. Fourteen SNPs in the NR1I2 gene have been reported, and the most heavily studied SNPs were rs3814055 and rs7643645. The pooled estimates did not exhibit any significant associations between SNPs rs3814055 and rs7643645 and the risk of ATDH (rs3814055: dominant model, OR = 1.00, 95% CI: 0.82‐1.22, P = 1.00; recessive model, OR = 1.17, 95% CI: 0.76‐1.78, P = .48; rs7643645: dominant model, OR = 1.04, 95% CI: 0.64‐1.68, P = .89; recessive model, OR = 0.98, 95% CI: 0.65‐1.49, P = .93). Subgroup analysis obtained similar negative results in Chinese patients, and the diagnostic criteria of ATDH may be the source of heterogeneity. Based on the meta‐analysis described in this report, we did not observe any association between NR1I2 gene polymorphisms and ATDH susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

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Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Cited by 24 publications

References 52 publications

Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury

Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

NR1I2 genetic polymorphisms and the risk of anti‐tuberculosis drug‐induced hepatotoxicity: A systematic review and meta‐analysis

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