This review discusses these emerging new paradigms of INH-induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis. Isoniazid (INH) remains a widely used and effective first-line agent for the treatment of tuberculosis, although newer drugs are being developed to face the challenge of emerging multidrug-resistant strains of Mycobacterium

tuberculosis.[1] Staurosporine cost Acute tuberculosis is mostly treated with a multidrug therapy approach (including rifampicin or pyrazinamide), but INH monotherapy is typically used in the treatment of latent tuberculosis. Shortly after its introduction to the market in 1952, INH was recognized to be associated with Saracatinib cost rare cases of liver injury, and the drug received a black box warning as early as 1969. The exact incidence of INH-induced liver injury is difficult to estimate retrospectively, mainly due to notorious underreporting and the contribution of comedications to these adverse effects.

However, recent comprehensive prospective studies that included patients from different countries have revealed that the incidence of serious INH-induced liver injury is well in the previously published range of 1–3% of treated (exposed) patients.[2-4] Thus, these numbers place INH among the top-ranking drugs regarding their potential to cause drug-induced liver injury (DILI), although the absolute numbers of INH-related DILI cases are smaller

than those of other drugs that are given to much larger patient populations. Despite extensive research over several decades, the underlying mechanisms of INH-induced DILI have remained poorly understood. One of the reasons is the complexity of these mechanisms and the difficulty to distinguish between drug-related mechanisms (that determine the hazard) and patient-related Dipeptidyl peptidase mechanisms (that determine the actual risk) (Fig. 1a). Traditionally, the drug-specific mechanisms (determined by the chemotype) have included the generation of reactive metabolites leading to hepatocellular injury, while the patient-specific determinants of susceptibility have long been considered to be genetic polymorphisms and other mutations in genes coding for some of the drug-metabolizing enzymes involved in the bioactivation and detoxication pathways of INH. However, recent analyses on mechanisms and risk factors associated with INH hepatotoxicity have revealed that there are still important gaps in our understanding of its pathogenesis;[5-7] therefore, these classical paradigms need to be revisited. For example, novel experimental data suggest that there may be previously unrecognized mechanisms, including INH-induced activation of the adaptive and innate immune system, disruption of endogenous metabolism, and mitochondrial dysfunction that may be implicated in INH hepatotoxicity.