WHAT IS KNOWN AND OBJECTIVE: Tuberculosis (TB) is a major cause of illness and death in developing countries. Hepatotoxicity is a serious side effect of antituberculosis treatment (ATT). NAT2, CYP2E1 and glutathione S-transferase (GST) gene polymorphisms may play an important role in ATT-induced hepatotoxicity. So, elucidating the genetics involved in anti-TB drug-induced hepatotoxicity in patients would be of utmost clinical significance. Therefore, the objective of the study was to elucidate the role of NAT2, CYP2E1 and GST gene polymorphisms in ATT-induced hepatotoxicity in North Indian patients. METHODS: Three hundred patients with pulmonary and extra-pulmonary TB were enrolled. Total genomic DNA was isolated from each patient's peripheral lymphocytes using phenol-chloroform method, and genetic polymorphic analysis for N-acetyltransferase 2 (NAT2), cytochrome P4502E1 (CYP2E1) and GST was performed by polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP). RESULTS AND DISCUSSION: Of the 300 patients, 185 were males and 115 females. Among them, 33 males and 22 females developed ATT-induced hepatotoxicity. There were significant increases in alanine aminotransferase, aspartate aminotransferase and bilirubin levels in patients with ATT-induced hepatotoxicity at 1 month of treatment. NAT2 5/7 and 6/7 were significantly higher in hepatotoxicity patients as compared to the non-hepatotoxicity group. c1/c1 allele of CYP2E1 gene was lower (50·9%) in ATT-induced hepatotoxicity patients as compared to non-hepatotoxicity patients (61·2%), whereas c1/c2 and c2/c2 alleles were higher, but not statistically significant. GSTM1 was significantly higher in hepatotoxicity patients as compared to non-hepatotoxicity patients, whereas GSTT1 and GSTT1/M1 were lower, but not statistically significant. WHAT IS NEW AND CONCLUSION: This study indicates that patients with slow-acetylator genotypes (NAT2 5/7, 6/7) and GSTM1 allele of GST enzyme were at higher risk of ATT-induced hepatotoxicity.
WHAT IS KNOWN AND OBJECTIVE:Tuberculosis (TB) is a major cause of illness and death in developing countries. Hepatotoxicity is a serious side effect of antituberculosis treatment (ATT). NAT2, CYP2E1 and glutathione S-transferase (GST) gene polymorphisms may play an important role in ATT-induced hepatotoxicity. So, elucidating the genetics involved in anti-TB drug-induced hepatotoxicity in patients would be of utmost clinical significance. Therefore, the objective of the study was to elucidate the role of NAT2, CYP2E1 and GST gene polymorphisms in ATT-induced hepatotoxicity in North Indian patients. METHODS: Three hundred patients with pulmonary and extra-pulmonary TB were enrolled. Total genomic DNA was isolated from each patient's peripheral lymphocytes using phenol-chloroform method, and genetic polymorphic analysis for N-acetyltransferase 2 (NAT2), cytochrome P4502E1 (CYP2E1) and GST was performed by polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP). RESULTS AND DISCUSSION: Of the 300 patients, 185 were males and 115 females. Among them, 33 males and 22 females developed ATT-induced hepatotoxicity. There were significant increases in alanine aminotransferase, aspartate aminotransferase and bilirubin levels in patients with ATT-induced hepatotoxicity at 1 month of treatment. NAT2 5/7 and 6/7 were significantly higher in hepatotoxicitypatients as compared to the non-hepatotoxicity group. c1/c1 allele of CYP2E1 gene was lower (50·9%) in ATT-induced hepatotoxicitypatients as compared to non-hepatotoxicitypatients (61·2%), whereas c1/c2 and c2/c2 alleles were higher, but not statistically significant. GSTM1 was significantly higher in hepatotoxicitypatients as compared to non-hepatotoxicitypatients, whereas GSTT1 and GSTT1/M1 were lower, but not statistically significant. WHAT IS NEW AND CONCLUSION: This study indicates that patients with slow-acetylator genotypes (NAT2 5/7, 6/7) and GSTM1 allele of GST enzyme were at higher risk of ATT-induced hepatotoxicity.
Authors: Min Zhang; Shuqiang Wang; Bob Wilffert; Rongsheng Tong; Dick van Soolingen; Susan van den Hof; Jan-Willem Alffenaar Journal: Br J Clin Pharmacol Date: 2018-10-03 Impact factor: 4.335