Toxicity mitochondrial

Oxidizible substrates from glycolysis, fatty acid or protein catabolism enter the mitochondrion in the form of acetyl-CoA, or as other intermediaries of the Krebs cycle, which resides within the mitochondrial matrix. Reducing equivalents in the form of NADH and FADH pass electrons to complex I (NADH-ubiquinone oxidore-ductase) or complex II (succinate dehydrogenase) of the electron transport chain, respectively. Electrons pass from complex I and II to complex III (ubiquinol-cyto-chrome c oxidoreductase) and then to complex IV (cytochrome c oxidase) which accumulates four electrons and then tetravalently reduces O2 to water. Protons are pumped into the inner membrane space at complexes I, II and IV and then diffuse down their concentration gradient through complex V (FoFi-ATPase), where their potential energy is captured in the form of ATP. In this way, ATP formation is coupled to electron transport and the formation of water, a process termed oxidative phosphorylation (OXPHOS). 

Much progress has been made in understanding the different mechanisms that can cause mitochondrial dysfunction, such as (i) uncoupling of electron transport from ATP synthesis by undermining integrity of inner membrane (ii) direct inhibition of electron transport system components (iii) opening of the mitochondrial permeability transition pore leading to irreversible collapse of the transmembrane potential and release of pro-apoptotic factors (iv) inhibition of the 

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Before an antiviral agent becomes a drug, advanced toxicity testing, pharmacological combination, and drug-interaction studies are needed. The use of new cell-based assays that can predict mitochondrial toxicity, lactic acidosis, peripheral neuropathy, anemia, hypersensitivity, lipodystrophy, and other potential side effects can alleviate these issues (Stuyver et al. 2002). 

Depending on the nature of the compound, the ddN analogues have been associated with varying toxic side effects such as bone marrow suppression (AZT), pancreatitis (ddl), hypersensitivity reactions (ABC), and neurologic complications consequently to mitochondrial toxicity (ddC), while others, such as 3TC and (-)FTC, have few, if any, side effects. 

However, not all effects of NRTls on mitochondria can be explained by the DNA polymerase y hypothesis. Other mechanisms, either secondary to or independent of inhibition of DNA polymerase y are involved in NRTI toxicity (Moyle 2000a, 2000b Lewis et al. 2003). AZT is a potent inhibitor of mitochondrial DNA polymerase y but does not cause neuropathy in HIV patients (Dalakas 2001). Keswani and colleagues showed that NRTls caused direct mitochondrial toxicity through... 

Hoschele D (2006) Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. Toxicol In Vitro 20(5) 535-546 Itescu S, Brancato LJ et al (1989) A sicca syndrome in HIV infection association with HLA-DR5 and CDS lymphocytosis. Lancet 2(8661) 466 68 Itescu S, Brancato LJ et al (1990) A diffuse infiltrative CDS lymphocytosis syndrome in human immunodeficiency virus (HIV) infection a host immune response associated with HLA-DR5. Ann Intern Med 112(1) 3-10... 

Lewis W, Dalakas MC (1995) Mitochondrial toxicity of antiviral drugs. Nat Med 1(5) 417 22 Lewis W, Day BJ et al (2003) Mitochondrial toxicity of NRTI antiviral drugs an integrated cellular perspective. Nat Rev Drug Discov 2(10) 812-822 Lin-Greenberg A, Taneja-Uppal N (1987) Dysautonomia and infection with the human immunodeficiency virus. Ann Intern Med 106(1) 167... 

D/C all antiretrovirals symptomatic support with fluids some patients require IV bicarbonate, hemodialysis, parenteral nutrition, or mechanical ventilation once syndrome resolves, consider using NRTIs with 4- mitochondrial toxicity (ABC, TDF, 3TC, or FTC) monitor lactate after restarting NRTIs some clinicians use NRTI-sparing regimens. 

Banki K, Elfarra AA, Lash LH, et al. 1986. Metabolism of S-(2-chloro-l,l,2-trifluoroethyl)-L- cysteine to hydrogen sulfide and the role of hydrogen sulfide in S-(2-chloro-l,l,2-trifluoroethyl)-L-cysteine-induced mitochondrial toxicity. Biochem Boughs Res Caiman 138 707-713. 

Glutathione has specific transporters for its entry into mitochondria (as has iron, see later) such that any defects in its transport into the mitochondria will be important contributing factors in precipitating mitochondrial toxicity. Evidence that dicarboxylate and 2-oxoglutamate may be carriers for glutathione into the mitochondria has recently been published (Chen et at, 2000). 

Tune, B.M., Fravert, D. and Hsu, C.Y. (1989). Oxidative and mitochondrial toxic effects of cephalosporin antibiotics in the kidney A comparative study of cephaloridine and cephaloglycine. Biochem. Pharmacol. 38 795-802. 

In rats administered 2-bromoethylamine, urinary aziridine accounted for 15-45% of the dose. The carbamate 11.135 was not detected in urine, whereas oxazolidin-2-one and a tertiary metabolite, 5-hydroxy oxazolidin-2-one, accounted for 0 - 20% and 2 - 12% of the dose, respectively [156], The innocuity of oxazolidin-2-one led to the suggestion that either aziridine or 2-bromoethylamine itself is responsible for mitochondrial toxicity. These studies show that the nephrotoxic 2-haloethylamines undergo two competitive cyclizations with halide elimination, one probably a reaction of toxification, the other clearly a reaction of detoxification. 

Lee, E.-W., Lai, Y, Zhang, H. and Unadkat, J.D. (2006) Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENTl) Implications for interspecies differences in mitochondrial toxicity of fialuridine. The Journal of Biologiccd Chemistry, 281 (24), 16700-16706. 

Biomarkers Translational safety biomarkers (e.g., mitochondrial toxicity can be detected in vitro and in vivo), phospholipidosis [37]... 

Fung, M., Thornton, A., Mybeck, K., Hsiao-Hui, W., Hornbuckle, K. and Muniz, E. (2001) Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets - 1960-1999. Drug Information Journal, 35, 293—317. Dykens, J.A. and Will, Y. (2007) The significance of mitochondrial toxicity testing in drug development. Drug Discovery Today, 12, 777-785. 

Amacher, D.E. (2005) Drug-associated mitochondrial toxicity and its detection. Current Medicinal Chemistry, 12 (16), 1829-1839. 

Marroquin, L.D. et al. (2007) Circumventing the Crabtree effect replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicological Sciences, 97 (2), 539-547. 

Lafeuillade, A., Hittinger, G. and Chadapaud, S. (2001) Increased mitochondrial toxicity with ribavirin in HIV/HCVcoinfection. Lancet, 357 (9252), 280-281. 

Hynes, J., Marroquin, L., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B. and Will, Y. (2006) Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicolo cal Sciences, 92 (1), 186-200. 

Milazzo, L, Piazza, M., Sangaletti, O., Gatti, N., Cappelletti, A., Adorni, F., Antinori, S., Galli, M., Moroni, M. and Riva, A. (2005) [13C]Methionine breath test a novel method to detect antiretroviral drug-related mitochondrial toxicity. Journal of Antimicrobial Chemotherapy, 55 (1), 84—89. 

Tenofovir is taken once daily and is generally well tolerated, perhaps because it produces less mitochondrial toxicity than the NRTIs. Nausea, vomiting, flatulence, and diarrhea occur in 10% or fewer patients. Resistance to tenofovir has been documented, and cross-resistance to NRTIs may occur. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

In the doses used for HBV infection, lamivudine has an excellent safety profile. Headache, nausea, and dizziness are rare. Co-infection with HIV may increase the risk of pancreatitis. No evidence of mitochondrial toxicity has been reported. 

Diuron Novascreen PBR TSPO Mitochondrial toxicity Binding 34.30 2.60... 

Diuron Cellumen Mitochondrial membrane potential (72 h) Mitochondrial toxicity Expression 99.90 7.58... 

Several pathophysiological mechanisms have been proposed, including adverse effects of protease inhibitors on hepatocyte and fat cell function (143), mitochondrial toxicity from nucleoside analogues (144), excess of reactive oxygen species (145), and cytokine-mediated events... 

This case demonstrates almost the full clinical spectrum of mitochondrial toxicity. 

There was significant improvement in signs of mitochondrial toxicity in 49 patients who switched from stavudine to abacavir compared with 63 patients who continued to take stavudine in a non-randomized study for 12 months (152). Only patients who remained on their assigned treatment were included in the analysis. Lactate concentrations were assessed at baseline, week 24, and week 48, and electrical bioimpedance was performed in 22 cases and 12 controls at baseline and week 48. There were significant falls in serum lactate concentrations at weeks 24 and 48 in cases compared with controls. Patients who switched had a trend towards fat gain, while controls had significant reductions in total body fat and percentage of body fat. 

The authors assumed a direct mitochondrial toxic effect of articaine, although this was disputed by others in correspondence (169). 

Lactic acidosis is a severe and potentially fatal form of mitochondrial toxicity. Metabolic stress or vitamin deficiencies (riboflavin, carnitine) might provoke it. There is suggestive evidence of clinical benefit with riboflavin therapy (846). 

Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999 354 1112-5. 

Moyle G. Mitochondrial toxicity hypothesis for lipoatro-phy a refutation. AIDS 2001 15 413-5. 

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