Isoniazid-Induced Liver Injury: Pharmacogenetic Aspects

Abstract

Inter-individual differences in anti-tuberculosis chemotherapy outcomes have been demonstrated in clinical practice, such as, achievement of intended therapeutic effect in some patients, and insufficiency or absence of response to treatment in others, with development of adverse drug reactions, especially, isoniazid-induced liver injury. Isoniazid-induced liver injuries are the main reason for isoniazid discontinuation, which further leads to considerably reduced effectiveness of anti-tuberculosis chemotherapy, increased relapse risk, and secondary drug-resistance of M. tuberculosis. Hepatotoxic reactions to chemotherapy are predicated by mutations in genes encoding enzymes participating in isoniazid biotransformation: N-acetyltransferase 2 (NAT2), cytochrome P450 2Е1, and glutathione-S-transferase.NAT2 gene polymorphism has been identified as risk factor for isoniazid hepatotoxicity. Nucleotide substitutions in NAT2 gene cause modification of enzyme protein structure, reduction of enzyme synthesis and alteration of its activity. Based on genetically-determined isoniazid acetylation rate, patients are referred to three acetylator types: rapid, intermediate, and slow. Correlations have been established in meta-reviews and systematic reviews between slow acetylator type and frequency of hepatotoxic reactions to isoniazid.Based on study findings, interrelation was shown between cytochrome P450 CYP2E1 gene polymorphism and increased risk of liver injury during chemotherapy with isoniazid. Contribution of GSTM1 and GSTT1 genotypes to isoniazid toxicity requires further exploration, as the obtained results were ambiguous and controversial.