Hepatic glutathione levels, effect

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]. 

Ethionine ingestion by rats resulted in an increased bile flow and a reduced excretion of BSP. After prolonged treatment, doses of BSP otherwise nontoxic were apparently lethal. Histological examination indicated proliferation of ductules (Bll). The effect of ethionine on BSP excretion is possibly due to reduced levels of ATP. However, hepatic glutathione levels are also reduced (H23). 

In one-, four- and 13-week studies, the effects of coumarin treatment were compared in male Sprague-Dawley rats, CD-I mice and Syrian hamsters. Rats were fed 0-0.75% coumarin for one and four weeks and 0.5% coumarin for 13 weeks. Mice and hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for one, four or 13 weeks. In the rat, coumarin caused dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis and bile duct proliferation and increases in serum bilirubin content and both serum and hepatic y-glutamyltranspeptidase activity. A sustained stimulation of hepatocyte replicative DNA synthesis was observed in rats treated for four and 13 weeks. Levels of total hepatic glutathione were increased approximately twofold, and there were statistically significant decreases in microsomal cytochrome P450 content and ethylmorphine 7V-demethylase activity. These effects were reduced or not observed in mice and hamsters (Lake Grasso, 1996). 

Studies in vivo with different A-nitrosamines and their effect on the glutathione levels in hepatocytes reveal that these compounds are inhibitors of the enzymatic mitochondrial activity. " The chemical stmcmre of the A-nitrosamines plays an essential role in the alteration of these hepatic levels, confirming the hepatotoxic activity developing these compounds in the organism. On the other hand, teratogenic effects caused by the activity of A-nitrosamines have been detected, particularly at the level of the central nervous system. ... 

Thomas, P., Wofford, H.W., 1984. Effects of metal and organic compounds on hepatic glutathione, cysteine and acid soluble thiol levels in mullet (Mugil cephalus L.). Toxicol. Appl. Pharmacol. 76, 172-182. 

The converse is true of drugs requiring metabolic activation for toxicity. For example, paracetamol is less hepatotoxic to newborn than to adult mice, as less is metabolically activated in the neonate. This is due to the lower levels of cytochromes P-450 in neonatal liver (Fig. 5.30). Also involved in this is the hepatic level of glutathione, which is required for detoxication. Although levels of this tripeptide are reduced at birth, development is sufficiently in advance of cytochrome P-450 levels to ensure adequate detoxication (Fig. 5.30). The same effect has been observed with the hepatotoxin bromobenzene. (For further details of paracetamol and bromobenzene see chap. 7.) Similarly, carbon tetrachloride is not hepatotoxic in newborn rats as metabolic activation is required for this toxic effect, and the metabolic capability is low in the neonatal rat. 

Zang et al [140] reported the liver protective effects of the saponins isolated from A. membranaceus and A. sieversianus against chemical injury induced by CCU, D-galactosamine and acetaminophen in mice. In all cases there were positive activities and the saponins inhibited the rise in SGPT levels, decreased the malondialdehyde (MDA) content and increased the glutathione reduced (GSH) concentration in mouse liver. The same compounds were also evaluated in cultured rat hepatocytes, and the results indicated that the activity may be due to to the antioxidative activity of the saponins, since the content of liver protein in treated mice was more than the control. Moreover, in all treated mice, the level of hepatic microsomal cytochrome P-450 was increased. The liver metabolism and immunoregulating action produced by saponins may be also involved in their hepato-protective effects. Similar results were obtained by Zhang et al [141] when they studied the activity in vitro and... 

In rats, hepatic ischaemia is associated with reduced ATP levels but normal lipid peroxide formation. Reperfusion gives a slow recovery of ATP levels, a reduction in endogenous vitamin E and glutathione, but an increase in lipid peroxidation. Vitamin-E-treated animals showed accelerated ATP synthesis with a suppression of the increased lipid peroxidation [ 170, l7l]. Ischaemia of liver tissue reduced the metabolism of xenobiotics. Vitamin E was protectant against this effect [172]. The protective effect is related to an increase in catalytic activity of cytochrome P-450, to antioxidant and membrane-stabilizing properties [173]. In kidney tissue, prophylactic injection of vitamin E and synthetic antioxidants prevented the development of lesions during acute renal ischaemia and subsequent reperfusion. These effects were related therefore to the vitamin s antioxidant ability. 

---