A study of genetic polymorphism underlying idiosyncratic hepatotoxicity due to anti-tuberculosis medications

Abstract

Anti-tuberculosis drug-induced liver injury is a rare but serious adverse drug reaction. This study aimed to identity specific genes conferring susceptibility to this serious adverse drug reaction, especially in relation to isoniazid treatment and to study the underlying mechanism for toxicity. Anti-tuberculosis drug-induced liver injury cases (n=26) and community controls (n=90) from Europe and South Asia were genotyped for polymorphisms in NAT2, GST genes, CYP2E1, PXR and SOD2. NAT2 slow acetylators were more susceptible to liver injury (OR=4.60; 95% CI=1.47-14.44). The GSTM1 null genotype was more common in cases than controls (OR=2.91; 95% CI=1.14-7.43). Risk of liver injury was significantly increased in subjects with combined NAT2 slow acetylator and GSTM1 null genotype (OR=3.71; 95% CI=1.48-9.31). No significant effects were seen for the other genotypes studied except that a GSTA4 haplotype was slightly more common in liver injury cases. The contribution of NAT2 genotype to isoniazid toxicity was examined using an in vitro overexpression approach. Stable expression of either NAT2*4 or NAT*5 constructs in HepG2 cells had small effects on reduced glutathione to oxidised glutathione ratio and apoptosis. These changes were consistent with higher NAT2 activity increasing isoniazid toxicity. In addition, overexpression and siRNA knockdown approaches showed protective roles for GSTA1 and A4 against isoniazid toxicity. The relevance of combinations of anti-tuberculosis drugs to overall toxicity was investigated by studies in human hepatocytes and LS180 cells. In the LS180 cells, rifampicin coadministation with isoniazid resulted in a small but significant decrease in both isoniazid and pyrazinamide toxicity. Studies on the isoniazid-rifampicin combination in human hepatocytes gave inconsistent findings but a decrease in cell toxicity due to isoniazid by pretreatment with rifampicin was seen in some donors. Increased expression of the carboxyesterase gene CES2 was seen in LS180 cells and in some hepatocytes and could represent a protective effect.