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

Anais da Academia Brasileira de Ciências

Tais C. Brito¹  Lia G. Possuelo¹  Andreia R.m. Valim¹  PÂmela F. Todendi¹  Andrezza W. Ribeiro¹  Tatiana S. Gregianini¹  Carla A. Jarczewski¹  Mara H. Hutz¹  Maria Lucia R. Rossetti¹  Arnaldo Zaha¹ 

关键词: hepatotoxicity;    isoniazid;    polymorphisms;    tuberculosis;    Hepatotoxicidade;    isoniazida;    polimorfismos;    tuberculose;   

DOI  :  10.1590/0001-3765201420130350

来源: SciELO

【 摘 要 】

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.

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