Glutathione hepatic

Acetaminophen, which depletes hepatic glutathione, does not potentiate the toxicity of methyl parathion in mice. A possible mechanism of action may be competition between acetaminophen and methyl parathion for mixed function oxidases and subsequent prevention of activation of methyl parathion to methyl paraoxon (Costa and Murphy 1984). Diethyl maleate, an agent that depletes cytosolic glutathione and is not an enzyme inducer, potentiates toxicity of methyl parathion in mice (Mirer et al. 1977). 

MARCH T H, JEFFERY E H and WALLIG M A (1998) The crucifetous nitrile, cramhene, induces rat hepatic and pancreatic glutathione S-transferases , Toxicol Sci, 42 82-90. 

Yasutake A, Hirayama K. 1994. Acute effects of methyhnercury on hepatic and renal glutathione metabolisms in mice. Arch Toxicol 68 512-516. 

Furthermore, depletion of hepatic GSH induced chemically or by fasting augmented hepatic I/R-induced enzyme release and promoted lipid peroxidation (Jennische, 1984 Stein et al., 1991) Benoit et al. (1992) have used portacaval-shunted rats as a model of chronic hepatic ischaemia, and were able to show decreases in total levels of SOD and xanthine dehydrogenase, but no significant change in catalase or glutathione peroxidase. 

Mitchell, J.R., follow, D.J., Potter, W.Z. Gillette, J.R. and Brodie, B.B. (1973b). Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther. 187, 211-217. 

Shaw, S., Rubin, K.P. and Lieber, C.S. (1983). Depressed hepatic glutathione and increased diene conjugation in alcoholic liver disease. Dig. Dis. Sci. 28, 585-587. 

Speisky, H., Bunou, D., Orrego, H. and Israel, Y. (1985). Lack of changes in diene conjugate levels following ethanol-induced glutathione depletion or hepatic necrosis. Res. Commun. Chem. Pathol. Pharmacol. 48, 77-90. 

Stein, H.J., Oosthuizen, M.M., Hinder, R.A. and Lamprechts, H. (1991). Oxygen free radicals and glutathione in hepatic ischaemia/reperfusion injury. J. Surg. Res. 50, 398-402. 

Bhuvaneswari, V., Velmurugan, B., and Nagini, S. 2002. Induction of glutathione-dependent hepatic biotransformation enzymes by lycopene in the hamster cheek pouch carcinogenesis model. J Biochem Mol Biol Biophys 6 257-260. 

P. H., Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues, J. Pharmacol. Exp. Ther. 1990, 253, 387-394. 

Li L, Lee TK, Meier PJ, Ballatori N. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatpl, the hepatic sinusoidal organic solute transporter. J Biol Chem 1998 273(26) 16184—16191. 

Haskovec C, Gut I, Volmerova D, et al. 1988. Acrylonitrile depletes glutathione without changing calcium sequestration in hepatic microsomes and mitochondria. Toxicology 48 87-92. 

In addition to the well-known iron effects on peroxidative processes, there are also other mechanisms of iron-initiated free radical damage, one of them, the effect of iron ions on calcium metabolism. It has been shown that an increase in free cytosolic calcium may affect cellular redox balance. Stoyanovsky and Cederbaum [174] showed that in the presence of NADPH or ascorbic acid iron ions induced calcium release from liver microsomes. Calcium release occurred only under aerobic conditions and was inhibited by antioxidants Trolox C, glutathione, and ascorbate. It was suggested that the activation of calcium releasing channels by the redox cycling of iron ions may be an important factor in the stimulation of various hepatic disorders in humans with iron overload. 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Vogiatzis, A.K. and N.S. Loumbourdis. 1998. Cadmium accumulation in liver and kidneys and hepatic metallothionein and glutathione levels in Rana ridibunda, after exposure to CdCl2. Arch. Environ. Contam. Toxicol. 34 64-68. 

Iscan, M., B.C. Eke, and T. Coban. 1993. Combined effects of cadmium and nickel on hepatic glutathione 5-transferases in rats. Comp. Biochem. Physiol. 104C 453-456. 

Kirby, G.M., J.R. Bend, I.R. Smith, and M.A. Hayes. 1990. The role of glutathione s-transferases in the hepatic metabolism of benzo[a]pyrene in white suckers (Catostomus commersoni) from polluted and reference sites in the Great Lakes. Comp. Biochem. Physiol. 95C 25-30. 

Hoffman, D.J., G.H. Heinz, and A.J. Krynitsky. 1989. Hepatic glutathione metabolism and lipid peroxidation in response to excess dietary selenomethionine and selenite in mallard ducklings. Jour. Toxicol. Environ. Health 27 263-271. 

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