Metabolism mitochondrial toxicity

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. 

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,... 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

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). 

Two HIV-1-positive women, both of whom had taken regimens containing stavudine and didanosine for at least 2 years, presented in the third trimester of pregnancy, one with acute lactic acidosis and one with acute pancreatitis and lactic acidosis (32). In the first case both mother and baby died. It is not known whether pregnancy is a risk factor for NRTI-induced lactic acidosis, perhaps in combination with riboflavin deficiency or a metabolic defect in the fetus, or whether NRTIs independently cause lactic acidosis through mitochondrial toxicity. 

As with any medication, adverse effects occur with antiretroviral agents that may limit the patient s ability to tolerate medication. Several important adverse effects have been recognized with the currently available antiretrovirals. These include mitochondrial toxicity with NRTIs, rash with NNRTIs, and metabolic perturbations with Pis. A discussion on the specific presentation and management of these adverse effects is beyond the scope of this chapter but can be found elsewhere. " ... 

Effects attributed to chlordane exposure include blood dyscrasia, hepatotoxicity, neurotoxicity, immunotoxicity and cancer. Possible mechanisms of toxicity relevant to all target organs include the ability of chlordane and its metabolites to bind irreversibly to cellular macromolecules, inducing cell death or disrupting normal cell function. In addition, chlordane may increase tissue production of superoxide, which can accelerate lipid peroxidation, disrupting the function of cellular and subcellular membranes. Chlordane induces its own metabolism to toxic intermediates, which may exacerbate its hepatotoxicity. This may involve suppression of hepatic mitochondrial energy metabolism. 

Will, Y, Dykens, J. (2014). Mitochondrial toxicity assessment in industry—a decade of technology development and insight. Expert Opinion in Drug Metabolism and Toxicology, 10, 1061-1067. 

Industrial Applications Colored bubbles - color filters liquid crystal displays light-emitting diodes luminescent materials " nanophotonic composites paints semiconductor electrodes solar cells Safety/Toxicity Acute toxicity aluminum toxicity cardiotoxicity cellular toxicity C5dotoxicity metabolic toxicity mitochondrial toxicity mutagenicity nephrotoxicity neurotoxicity ocular toxicity phototoxicity reproductive toxicity ... 

Mechanistic studies have shown that TBT and certain other forms of trialkyltin have two distinct modes of toxic action in vertebrates. On the one hand they act as inhibitors of oxidative phosphorylation in mitochondria (Aldridge and Street 1964). Inhibition is associated with repression of ATP synthesis, disturbance of ion transport across the mitochondrial membrane, and swelling of the membrane. Oxidative phosphorylation is a vital process in animals and plants, and so trialkyltin compounds act as wide-ranging biocides. Another mode of action involves the inhibition of forms of cytochrome P450, which was referred to earlier in connection with metabolism. This has been demonstrated in mammals, aquatic invertebrates and fish (Morcillo et al. 2004, Oberdorster 2002). TBTO has been shown to inhibit P450 activity in cells from various tissues of mammals, including liver, kidney, and small intestine mucosa, both in vivo and in vitro (Rosenberg and Drummond 1983, Environmental Health Criteria 116). 

Lash LH, Xu Y, Elfarra AA, et al. 1995. Glutathione-dependent metabolism of trichloroethylene in isolated liver and kidney cells of rats and its role in mitochondrial and cellular toxicity. Drug Metabolism and Disposition 23 846-853. 

Since the tragic human exposure to diethyltin salts for the therapy of an infectious skin disease by Staphylococcus in France in the 1950s, the toxic and biochemical effects of many of these derivatives have been explored. Di- and tri-ethyltin salts have been demonstrated to have pronounced effects on intermediary metabolism in brain and liver. These effects have been suggested to be due to inhibition of the mitochondrial functions9,27. 

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

There are at least three ways in which mitochondrial ATP generation can be impaired mutations in mitochondrial DNA, mutations in nuclear DNA and effects of toxic compounds. The reactions in mitochondrial metabolism that are affected by some toxic compounds are described in Appendix 9.12. 

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