Mitochondrial bioactivation of cysteine S-conjugates and 4-thiaalkanoates: implications for mitochondrial dysfunction and mitochondrial diseases.
The toxicity of most drugs and chemicals is associated with their enzymatic conversion to toxic metabolites. Bioactivation reactions occur in a range of organs and organelles, including mitochondria. The toxicity of haloalkene-derived cysteine S-conjugates and related 4-thiaalkanoates is associated with their mitochondrial bioactivation. Toxic cysteine S-conjugates are formed by the glutathione S-transferase-catalyzed addition of glutathione to haloalkenes to give glutathione S-conjugates, which are hydrolyzed by gamma-glutamyltransferase and dipeptidases. Mitochondrial cysteine conjugate beta-lyase-catalyzed bioactivation of cysteine S-conjugates affords unstable alpha-halothiolates. Haloalkene-derived 4-thiaalkanoates, which are analogs of cysteine S-conjugates that lack an alpha-amino group, undergo bioactivation by the enzymes of fatty acid beta-oxidation to give 3-hydroxy-4-thiaalkanoates that eliminate alpha-halothiolates. alpha-Halothiolates yield alkylating and acylating agents that interact with cellular macromolecules and thereby cause cell damage. Mitochondrial dysfunction is the hallmark of cysteine S-conjugate-induced cytotoxicity: decreased respiration, decreased ATP and total adenine nucleotide concentrations, depletion of the mitochondrial glutathione content, perturbations in cellular Ca2+ homeostasis, and damage to the mitochondrial genome are seen with cysteine S-conjugates. Similar changes are observed with cytotoxic 4-thiaalkanoates, but inhibition of the medium-chain acyl-CoA dehydrogenase and hypoglycemia are also observed.
Anders
M W
MW
Department of Pharmacology, University of Rochester, New York 14642, USA.
D000818:Animals; D001711:Biotransformation; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000378:metabolism* / Q000633:toxicity*; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D017240:Mitochondrial Myopathies / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects
D006846:Hydrocarbons, Halogenated; D005982:Glutathione Transferase; D003545:Cysteine