However, how exactly these SNPs are positively correlated with DILI remains unknown. Finally, similar to other drugs that have been implicated with DILI, INH liver injury has been associated with certain HLA haplotypes. Specifically, the absence of HLA-DQA1*0102 (odds ratio 4) and the presence of HLA-DQB1*0201 (odds ratio 1.9) were independent risk factors for INH-associated DILI.[78] Despite this compelling positive correlation, the underlying

role of the adaptive immune system in INH-induced DILI is still unclear.[79] Hedgehog antagonist Although it has been increasingly recognized that the host-specific intestinal microbiome composition (enterotype) can influence the toxic response to drugs,[80, 81] the role of changes in the microbiome as a determinant of susceptibility to DILI has been insufficiently explored. One study with germ-free and normal rats that received hydrazine (60 mg/kg p.o.) has analyzed urine and plasma profiling by 1H-NMR spectroscopy to determine a potential role of gut bacteria.[82] The authors found that the hepatic toxicity of hydrazine was more severe in animals devoid of gut bacteria, while conventional rats developed only minimal toxicity. The differences were not

due to altered selleck chemicals metabolism of hydrazine, but rather to a differential response to the challenge. Specifically, the germ-free animals excreted 2-oxoglutarate in the urine at higher rates, while succinate levels

were lower. This suggests a differential role of intestinal bacteria in regulating the host’s energy homeostasis in the liver; however, the overall role of changes in the microbiome as a determinant of susceptibility to INH-induced DILI is still unclear. Two types 上海皓元 of cotreatment with other drugs may increase the risk for INH-associated DILI. First, other antitubercular drugs (rifampicin, pyrazinamide) have been implicated in causing additive or synergistic effects on liver injury.[7] In animal models, when combination treatments are being used, it is often not possible to exactly determine the relative contribution to liver injury by the individual drugs. For the widely used INH/rifampicin co-exposure model, however, a recent study has revealed that the PXR-mediated hepatotoxic effects seem to be attributable to rifampicin, and not to PXR-mediated alterations in INH metabolism.[25] The second type of cotreatment that may increase the sensitivity to INH-induced DILI are drugs not related to antitubercular activity. For example, INH is often combined with antiretroviral drugs, as immunocompromised patients with HIV infections are more prone to be infected with tuberculosis.