Association of GST null genotypes with anti-tuberculosis drug induced hepatotoxicity in Western Indian population

• Published in: Annals of hepatology Vol. 12; no. 6; pp. 959 - 965
• Main Authors: Gupta, Vinod H, Singh, Meenakshi, Amarapurkar, Deepak N, Sasi, Preetha, Joshi, Jyotsna M, Baijal, Rajiv, H R, Praveen Kumar, Amarapurkar, Anjali D, Joshi, Kalpana, Wangikar, Pramod P
• Format: Journal Article
• Language: English
• Published: Mexico Elsevier 01.11.2013
• Subjects: Adult; Antitubercular Agents - adverse effects; Antitubercular Agents - metabolism; Case-Control Studies; Case-control study; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - epidemiology; Chemical and Drug Induced Liver Injury - genetics; Drug induced hepatotoxicity; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Homozygote; Homozygous null mutation; Humans; India - epidemiology; Male; Middle Aged; Pharmacogenetics; Phase II enzymes; Phenotype; Polymorphism, Genetic; Prospective Studies; Risk Factors; Young Adult
• ISSN: 1665-2681
• DOI: 10.1016/s1665-2681(19)31302-x

The first line anti-tubercular (anti-TB) treatment normally involves isoniazid, rifampicin, pyrazinamide, and ethambutol. Clearance of these drugs depends on the activity of several enzymes such as N-acetyl transferase 2, cytochrome P450 oxidase and glutathione S-transferase (GST). Some of these enzymes are highly polymorphic leading to significant inter-individual variation in their activity thereby increasing the risk of drug induced hepatotoxicity (DIH). To investigate the possible association of anti-TB DIH with genetic polymorphism of GST genes in Western Indian population. A prospective case-control study was undertaken on patients who received anti-TB treatment. Cases (n = 50) were distinguished from controls (n = 246) based on occurrence of DIH during anti-tubercular treatment. A multiplex polymerase chain reaction was employed to identify homozygous null mutation at GSTM1 and GSTT1 loci. Results. Homozygous null mutation in GSTM1 gene alone or in both GSTM1 and T1 genes was found to be significantly associated with anti-TB DIH at p < 0.02 and p < 0.007, respectively, in our study population. This is the first study to report GSTM1 null and combined GSTM1 and T1 null genotypes to be risk factors of anti-TB DIH in Western Indian population. Screening of patients for these genotypes prior to anti-TB regimen would provide better control of hepatotoxicity.