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

Overview

Journal Sci Rep

Specialty Science

Date 2019 Feb 20

PMID 30778091

Citations 14

Authors

Yu Wang

Xi Xiang

Wei-Wei Huang

Andrew J Sandford

Shou-Quan Wu

Miao-Miao Zhang

Ming-Gui Wang

Guo Chen

Jian-Qing He

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Standard Protocols for Characterising Primary and In Vitro-Generated Human Hepatocytes.

Heydari Z, Gramignoli R, Piryaei A, Zahmatkesh E, Pooyan P, Seydi H J Cell Mol Med. 2025; 29(3):e70390.

PMID: 39910642 PMC: 11798750. DOI: 10.1111/jcmm.70390.

Roles of and polymorphisms in the susceptibility to antituberculosis drug-induced liver injury in China: a case‒control study.

Xu X, Chen R, Lu L, Cheng J, He X, Pan H Front Genet. 2024; 15:1428319.

PMID: 39512799 PMC: 11541836. DOI: 10.3389/fgene.2024.1428319.

Importance of Pharmacogenetics and Drug-Drug Interactions in a Kidney Transplanted Patient.

Concha J, Sanguesa E, Saez-Benito A, Aznar I, Berenguer N, Saez-Benito L Life (Basel). 2023; 13(8).

PMID: 37629484 PMC: 10455535. DOI: 10.3390/life13081627.

Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review.

Zhuang X, Li L, Liu T, Zhang R, Yang P, Wang X Front Pharmacol. 2022; 13:1037814.

PMID: 36299895 PMC: 9589499. DOI: 10.3389/fphar.2022.1037814.

Population Pharmacokinetic Modeling of Bedaquiline among Multidrug-Resistant Pulmonary Tuberculosis Patients from China.

Zou J, Chen S, Rao W, Fu L, Zhang J, Liao Y Antimicrob Agents Chemother. 2022; 66(10):e0081122.

PMID: 36106884 PMC: 9578397. DOI: 10.1128/aac.00811-22.

References

Gupta S, GRIECO M, SIEGEL I . Suppression of T-lymphocyte rosettes by rifampin. Studies in normals and patients with tuberculosis. Ann Intern Med. 1975; 82(4):484-8. DOI: 10.7326/0003-4819-82-4-484. View

Chowdhury A, Santra A, Kundu S, Mukherjee A, Pandit A, Chaudhuri S . Induction of oxidative stress in antitubercular drug-induced hepatotoxicity. Indian J Gastroenterol. 2001; 20(3):97-100. View

Sharma S, Balamurugan A, Saha P, Pandey R, Mehra N . Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med. 2002; 166(7):916-9. DOI: 10.1164/rccm.2108091. View

Tirona R, Lee W, Leake B, Lan L, Cline C, Lamba V . The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med. 2003; 9(2):220-4. DOI: 10.1038/nm815. View

Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D . Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003; 167(11):1472-7. DOI: 10.1164/rccm.200206-626OC. View

Hahn L, Ritchie M, Moore J . Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics. 2003; 19(3):376-82. DOI: 10.1093/bioinformatics/btf869. View

Kamiya A, Inoue Y, Gonzalez F . Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Hepatology. 2003; 37(6):1375-84. DOI: 10.1053/jhep.2003.50212. View

Lee W . Drug-induced hepatotoxicity. N Engl J Med. 2003; 349(5):474-85. DOI: 10.1056/NEJMra021844. View

Swales K, Negishi M . CAR, driving into the future. Mol Endocrinol. 2004; 18(7):1589-98. DOI: 10.1210/me.2003-0397. View

10.

Shakya R, Rao B, Shrestha B . Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors. Ann Pharmacother. 2004; 38(6):1074-9. DOI: 10.1345/aph.1D525. View

11.

Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2004; 21(2):263-5. DOI: 10.1093/bioinformatics/bth457. View

12.

Shi Y, He L . SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005; 15(2):97-8. DOI: 10.1038/sj.cr.7290272. View

13.

Blumberg H, Leonard Jr M, Jasmer R . Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA. 2005; 293(22):2776-84. DOI: 10.1001/jama.293.22.2776. View

14.

Ikeda S, Kurose K, Jinno H, Sai K, Ozawa S, Hasegawa R . Functional analysis of four naturally occurring variants of human constitutive androstane receptor. Mol Genet Metab. 2005; 86(1-2):314-9. DOI: 10.1016/j.ymgme.2005.05.011. View

15.

Gong H, Singh S, Singh S, Mu Y, Lee J, Saini S . Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells. Mol Endocrinol. 2005; 20(2):279-90. DOI: 10.1210/me.2005-0205. View

16.

Hunt C, Westerkam W, Stave G . Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992; 44(2):275-83. DOI: 10.1016/0006-2952(92)90010-g. View

17.

Zhou C, Tabb M, Nelson E, Grun F, Verma S, Sadatrafiei A . Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest. 2006; 116(8):2280-2289. PMC: 1501109. DOI: 10.1172/JCI26283. View

18.

Yuan H, Chiou J, Tseng W, Liu C, Liu C, Lin Y . FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res. 2006; 34(Web Server issue):W635-41. PMC: 1538865. DOI: 10.1093/nar/gkl236. View

19.

Timsit Y, Negishi M . CAR and PXR: the xenobiotic-sensing receptors. Steroids. 2007; 72(3):231-46. PMC: 1950246. DOI: 10.1016/j.steroids.2006.12.006. View

20.

Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E . Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos. 2007; 36(1):169-81. DOI: 10.1124/dmd.107.016600. View