Membrane potential of hepatic mitochondria after acute cocaine administration in rats—The role of mitochondrial reduced glutathione

✍ Scribed by A Masini; D Gallesi; F Giovannini; T Trenti; D Ceccarelli

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 223 KB
• Volume: 25
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510250221

✦ Synopsis

patic lesion resulting from cocaine in humans, coagulative Cocaine hepatotoxicity may be mediated by oxidative necrosis, is similar to the one described in experimental anidamage, possibly involving mitochondrial injury. The efmals. 6,7 fect of an acute dose of cocaine in rats on the mitochon-Cocaine is metabolized mainly via hydrolytic and oxidative drial level of reduced glutathione, nicotinamide adenine mechanisms. Although the former route is quantitatively the dinucleotide (NADH) and nicotinamide adenine dinuclemost important, the minor oxidative pathway, catalyzed by otide phosphate (NADPH), important determinants in specific P-450 isoforms, seems to be responsible for the hepacellular defense against oxidative stress, was investitotoxicity of cocaine. [8][9][10][11][12] Two basic mechanisms have been gated. Under these conditions, the extent of lipid peroxisuggested to account for cell injury: the induction of lipid dation was assessed as thiobarbituric acid reactive subperoxidation of cell membranes, 13 and covalent interaction of stances formation and the energy transducing capability of the inner mitochondrial membrane was evaluated by a chemical reactive cocaine intermediate with critical tissue membrane potential measurements. Female Wistar alproteins. 14,15 However, the relative contribution of these bino rats were given an acute 50 mg/kg intraperitoneal mechanisms and the sequence of early events during cocainedose of cocaine and, 6 hours later, hepatic and mitochoninduced hepatotoxicity, thus far, remain unclear. 9 The Ndrial biochemical analyses were made. Rats adminisoxidative pathway, represents the bioactivating cascade tered intraperitoneally, 7.5 hours before the sacrifice, a leading to cocaine hepatotoxicity. 11,12 Among the possible biospecific inhibitor of glutathione synthesis, L-buthioninemechanisms by which cocaine exerts its cytotoxic effects, di-(S,R)-sulphoximine, either alone or in combination with rect oxidative damage by reactive oxygen species appears to cocaine, underwent in parallel the same determinations. be the most important. It has been suggested that the pres-Cocaine intoxication did not impair mitochondrial funcence of a futile redox cycling between norcocaine nitroxide tions, although a significant increase of lipid peroxidaand N-hydroxynorcocaine generates superoxide anion radition occurred. By contrast the combination of L-buthiocals and H 2 O 2 . 8,16 Meanwhile, this mechanism has been quesnine-(S,R)-sulphoximine with cocaine induced a severe tioned by clearly demonstrating that neither cocaine niderangement of mitochondrial functional efficiency, a troxide nor N-hydroxynorcocaine is associated with the large depletion of reduced glutathione, and a further enformation of superoxide. 17 Recent work, using luminol-enhancement of lipid peroxidation. The mitochondrial hanced chemiluminesence, has shown that the interaction of functional anomalies were largely restored by the use of cocaine with hepatocellular mono-oxygenases produces H 2 O 2 cyclosporin A, ethyleneglycotetraacetic acid (EGTA) and and/or superoxide anions. 18 Therefore, oxidant stress, includglutathione methylmonoester. A nonspecific calcium deing lipid peroxidation, has been implicated in the pathogenependent inner membrane permeabilty transition (pore sis of cocaine-induced liver disease, although a causal role opening) accounted for the partial loss of mitochondrial for this process has not been established. [11][12][13]19,20 In this vein, coupled functions at a period of cocaine intoxication it has been shown that reduced glutathione (GSH) plays a when no cell damage occurred. The level of mitochonpivotal protective role against cocaine-induced hepatic indrial glutathione played a critical role in protecting injury. 11,12,19,20 In fact, GSH may act both as a nucleophilic scavner membrane functional integrity against cocaine-inenger, converting electrophilic metabolites to thioether comduced oxidative stress. (HEPATOLOGY 1997;25:385-390.) pounds and as a substrate in degradation of hydroperoxides. 21 On the basis of indirect evidence, the proposal has been Acute cocaine intoxication is predominantly associated made that mitochondria may represent an important target with effects on cardiovascular, neuromuscular, and central for cocaine hepatotoxicity. 18,20,22 However, direct evidence nervous systems. 1 Increasing clinical evidence indicates that supporting this proposal is still lacking. In fact inconsistent cocaine is also potentially hepatotoxic. [2][3][4][5] The principal heresults about the effects of cocaine on structure and function of liver mitochondria have been obtained by different authors under similar experimental conditions both, in vivo and in Abbreviations: GSH, reduced glutathione; NADH, reduced nicotinamide adenine nucleovitro. 6,23,24 Furthermore, no work has been done to define the tide; NADPH, reduced nicotinamide adenine nucleotide phosphate; BSO, L-buthionine-(S,R)-sulphoximine; TPP / , tetraphenylphosphonium chloride; GSSG, oxidized glutathione; effect of cocaine on the small but vital mitochondrial pool of GSH-ME, glutathione methyl monoester; FCCP, carbonylcyanide-P-trifluoromethoxyphe-GSH which protects cell integrity against oxidant stress. 25,26 nylhydrazone; EGTA, ethylene glycol-bis(b-aminoethyl ether)-N,N,N,N-tetraacetic acid; Large interspecies, interstrain, sex, and age-dependent TBA-RS, thiobarbituric acid reactive substances.

From the Dipartmento di 1 Scienze Biodemiche, Sezione di Patologia Generale e 2 Medi-variations may account for the controversial data so far recina Interna,