Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I.

Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.

Bypassing the compromised mitochondrial electron transport with methylene blue alleviates efavirenz/isoniazid-induced oxidant stress and mitochondria-mediated cell death in mouse hepatocytes.

Efavirenz (EFV) is an anti-retroviral drug frequently combined with isoniazid (INH) to treat HIV-1/tuberculosis co-infected patients. Both drugs have been associated with idiosyncratic liver injury (DILI), but combined anti-retroviral and anti-tubercular therapy can increase the risk for DILI as compared to either drug class alone. Because both EFV and INH have been implicated in targeting mitochondria, we aimed at exploring whether the two drugs might cause synergistic effects on the electron transport chain.

Targeting mitochondria with methylene blue protects mice against acetaminophen-induced liver injury.

Unlabelled: Acetaminophen (APAP) overdose is a frequent cause of drug-induced liver injury and the most frequent cause of acute liver failure in the Western world. Previous studies with mouse models have revealed that impairment of mitochondrial respiration is an early event in the pathogenesis, but the exact mechanisms have remained unclear, and therapeutic approaches to specifically target mitochondria have been insufficiently explored. Here, we found that the reactive oxidative metabolite of APAP, N-acetyl-p-benzoquinoneimine (NAPQI), caused the selective inhibition of mitochondrial complex II activity by >90% in both mouse hepatic mitochondria and yeast-derived complexes reconstituted into nanoscale model membranes, as well as the decrease of succinate-driven adenosine triphosphate (ATP) biosynthesis rates.

Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress.

Idiosyncratic drug-induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient-specific and drug-specific mechanisms) leading to DILI are poorly understood. Among the patient-specific determinants of susceptibility to INH-associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug-metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial.

Isoniazid-induced cell death is precipitated by underlying mitochondrial complex I dysfunction in mouse hepatocytes.

Isoniazid (INH) is an antituberculosis drug that has been associated with idiosyncratic liver injury in susceptible patients. The underlying mechanisms are still unclear, but there is growing evidence that INH and/or its major metabolite, hydrazine, may interfere with mitochondrial function. However, hepatic mitochondria have a large reserve capacity, and minor disruption of energy homeostasis does not necessarily induce cell death.

Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics.

1.  We have previously demonstrated that a small molecule inhibitor of bacterial β-glucuronidase (Inh-1; [1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]) protected mice against diclofenac (DCF)-induced enteropathy. Here we report that Inh-1 was equally protective against small intestinal injury induced by other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin (10 mg/kg, ip) and ketoprofen (100 mg/kg, ip).

Correlation of metabolism/hypoxia markers and fluorodeoxyglucose uptake in oral squamous cell carcinomas.

Objective: The objective of this study was to analyze the relationship between the uptake of (18)F-2-fluoro-2-deoxy-d-glucose (FDG) by positron emission tomography-computerized tomography (PET-CT) and glucose metabolism/hypoxia markers in oral squamous cell carcinoma (OSCC).

Study Design: Thirty-six patients with OSCC (tongue [n = 23], buccal mucosa [n = 7], and floor of the mouth [n = 6]) were assessed and underwent incisional biopsy and subsequently received FDG-PET-CT. Expressions of hypoxia-inducible factor 1α (HIF-1α), glucose transporter protein 1 (GLUT-1), hexokinase-II (HK-II), and glucose-6-phosphatase (G6Pase) were immunohistochemically quantified, and FDG uptake was evaluated by the maximum standardized uptake values (SUV(max)) at the primary tumor site.

Inhibition of mitochondrial membrane bound-glutathione transferase by mitochondrial permeability transition inhibitors including cyclosporin A.

Aims: Effect of mitochondrial permeability transition (MPT) inhibitors on mitochondrial membrane-bound glutathione transferase (mtMGST1) activity in rat liver was investigated in vitro.

Main Methods: When mitochondria were incubated with MPT inhibitors, mtMGST1 activity was decreased dose dependently and their 50% inhibition concentration (IC(50)) were 1.2 microM (cyclosporin A; CsA), 31 microM (bongkrekic acid; BKA), 1.

Contribution of liver mitochondrial membrane-bound glutathione transferase to mitochondrial permeability transition pores.

We recently reported that the glutathione transferase in rat liver mitochondrial membranes (mtMGST1) is activated by S-glutathionylation and the activated mtMGST1 contributes to the mitochondrial permeability transition (MPT) pore and cytochrome c release from mitochondria [Lee, K.K., Shimoji, M.

Novel function of glutathione transferase in rat liver mitochondrial membrane: role for cytochrome c release from mitochondria.

Microsomal glutathione transferase (MGST1) is activated by oxidative stress. Although MGST1 is found in mitochondrial membranes (mtMGST1), there is no information about the oxidative activation of mtMGST1. In the present study, we aimed to determine whether mtMGST1 also undergoes activation and about its function.