For example, a recent study found that cotreatment of transgenic (humanized) mice with INH and rifampicin for 4 weeks (400 mg/L INH in the drinking water and 100 mg/kg rifampicin www.selleckchem.com/products/Romidepsin-FK228.html in the diet) caused an accumulation of protoporphyrin IX in the liver,[25] associated with mild, but significant increases in plasma ALT. This was mediated via the human PXR receptor, which led to a transcriptional upregulation of porphyrin biosynthesis. Interestingly, protoporphyrin has been related to hepatotoxicity; in fact, protoporphyrin IX is an endogenous ligand of the peripheral benzodiazepine receptor that can activate the induction of the mitochondrial permeability

transition, which in turn leads to cell necrosis.[54] Because oxidant stress is an imbalance between the overall pro-oxidant and anti-oxidant activity, INH-induced oxidant stress could be the result of either increased pro-oxidant levels or an impairment of the anti-oxidant defense systems. For INH, there are several possible modes of how reactive oxygen species (ROS) could

be generated. First, hydrazine and hydrazide derivatives have the potential to directly reduce molecular oxygen to superoxide (leaving behind a hydrazine radical).[55] These compounds can potentially damage the prosthetic group on many enzymes and cause degradation of polypeptide chains. Second, a burst of ROS can be generated by cells of the innate immune system, e.g. during an http://www.selleckchem.com/products/poziotinib-hm781-36b.html inflammatory response. To model this situation, hepatocytes were cotreated with nontoxic levels of H2O2 and INH;[56] such cotreated cells indeed became more sensitive (2-fold) to INH. find more Because the toxicity was 1-aminobenzotriazole (ABT)-sensitive (ABT is a pan-CYP inhibitor), it was concluded by the authors that CYPs were involved in the toxicity. However, because ABT is

also a potent inhibitor of NAT,[57] an alternative interpretation could involve a shift of the metabolism of INH from N-acetylation towards increased hydrolysis, thus generating hydrazine. Indeed, because the toxicity was BNPP-sensitive, it seems likely that hydrazine, rather than the parent INH, was responsible for the acute toxicity. Consistent with this concept is the findings that the toxicity of hydrazine was potentiated (16-fold) in the presence of an H2O2-generating system. Third, ROS could be generated by the mitochondrion. In line with this, increased levels of mitochondria-targeted hydroethidine-derived fluorescence were detected in cultured mouse hepatocytes exposed to INH.[18] However, the mechanistic significance of this increase is not clear from these in vitro studies. The role of oxidant stress is more convincing in animal models of INH/rifampicin cotreatment (although any observed effect cannot be easily attributed to either one of the two drugs).