Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Tais C Brito,Lia G Possuelo,Andrezza W Ribeiro,Mara H Hutz,Tatiana S Gregianini,Pâmela F Todendi,Andreia R.M Valim,Maria Lucia R Rossetti,Arnaldo Zaha,Carla A Jarczewski

doi:10.1590/0001-3765201420130350

Abstract

Anti-tuberculosis drug-induced hepatitis (ATD- induced hepatitis) has been linked to polymorphisms in genes encoding drug metabolizing enzymes. N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase (loci GSTM1 and GSTT1) are involved in the metabolism of isoniazid, the most toxic drug for the treatment of tuberculosis (TB). This study was designed to determine the frequency and to evaluate whether polymorphisms at CYP2E1, GSTM1 and GSTT1 genes are associated with drug response, as well as to identify clinical risk factors for ATD-induced hepatitis. A total of 245 Brazilian patients undergoing treatment for TB were genotyped using polymerase chain reaction and restriction fragment length polymorphism and sequencing methods. The frequencies of the CYP2E1 polymorphic alleles RsaI, PstI and DraI are 8%, 8.5% and 12%, respectively. GSTM1 and GSTT1 genes are deleted in 42.9% and 12.4% of the population, respectively. Fifteen patients (6.1%) developed hepatotoxicity. Clinical (HIV, female sex and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing ATD-induced hepatitis in this population. Genotyping for GSTM1 and GSTT1 showed no influence on drug response.

Highlights

Anti-tuberculosis drug-induced hepatitis (ATDinduced hepatitis) is an important clinical problem, being the most severe adverse effect during tubercu losis (TB) treatment (Tostmann et al 2008, Walker et al 2009, Cai et al 2012)
All of them have had their treatment switched to streptomycin (SM), INH and EMB, an alternative treatment to RMP, INH and PZAHZ used in Rio Grande do Sul in the presence of a hepatite induzida por drogas (ATD)-induced hepatitis
Our study shows the frequency of polymorphisms in cytochrome P450 2E1 (CYP2E1), GSTM1 and GSTT1, their association with ATD-induced hepatitis and clinical risk factors

Summary

Introduction

Anti-tuberculosis drug-induced hepatitis (ATDinduced hepatitis) is an important clinical problem, being the most severe adverse effect during tubercu losis (TB) treatment (Tostmann et al 2008, Walker et al 2009, Cai et al 2012). Patients often suffer adverse drug reactions (ADR) and it is of increasing concern the fact that hepatotoxicity may be due to additive or synergistic effects of INH and RMP (Yew and Leung, 2006). INH is first acetylated by N-acetyltransferase 2 (NAT2) into acetylhydrazine, oxidized into toxic intermediaries by cytochrome P450 2E1 (CYP2E1) (Huang et al 2003, Chamorro et al 2013). Our previous study of NAT2 polymorphism demonstrated that a slow acetylation profile is associated to ATD-induced hepatitis (Possuelo et al 2008)

Methods

Results

Conclusion