Role of mammalian cytosolic molybdenum Fe-S flavin hydroxylases in hepatic injury.

The study was designed to investigate the role of molybdenum iron-sulfur flavin hydroxylases in the pathogenesis of liver injuries induced by structurally and mechanistically diverse hepatotoxicants. While carbon tetrachloride (CCl4), thioacetamide (TAA) and chloroform (CHCl3) inflict liver damage by producing free radicals, acetaminophen (AAP) and bromobenzene (BB) exert their effects by severe glutathione depletion. Appropriate doses of these compounds were administered to induce liver injury in rats. The activities of the Mo-Fe-S flavin hydroxylases were measured and correlated with the biochemical markers of hepatic injury. The activity levels of the anti-oxidative enzymes and glutathione redox cycling enzymes were also determined. The treatment of rats with the hepatotoxins that inflict liver injury by generating free radicals (CCl4, TAA, CHCl3) had elevated activity levels of hepatic Mo-Fe-S flavin hydroxylases (p<0.05). Specific inhibition of these hydroxylases by their common inhibitor, sodium tungstate, suppresses biochemical and oxidative stress markers of hepatic tissue damage. On the contrary, Mo-Fe-S flavin hydroxylases did not show any change in animals receiving AAP and BB. Correspondingly, sodium tungstate could not attenuate damage in AAP and BB treated groups of rats. The study concludes that Mo-Fe-S hydroxylases contribute to the hepatic injury inflicted by free radical generating agents and does not play any role in hepatic injury produced by glutathione depleting agents. The study has implication in understanding human liver diseases caused by a variety of agents, and to investigate the efficacy of the inhibitors of Mo-Fe-S flavin hydroxylases as potential therapeutic agents.

Boron ameliorates fulminant hepatic failure by counteracting the changes associated with the oxidative stress.

Boron has well-defined biological effects and may be of therapeutic benefit. In the current paper, the effect of boron in the form of borax was tested in experimental animal model of fulminant hepatic failure (FHF). The syndrome was induced in female Wistar rats by three consecutive daily intraperitoneal injections of thioacetamide (400 mg/kg). In the treatment groups, rats received borax (4.0 mg/kg) orally for three consecutive days followed by thioacetamide. The group administered with thioacetamide plus vehicle, and the borax alone treated rats served as controls. In all groups, rats were terminated 4 h after administering the last dose of thioacetamide, and the tissue/serum was used to measure hepatic levels of thiobarbituric acid reactive substances, reduced glutathione, and various enzymes associated with oxidative stress including peroxide metabolizing enzymes and xanthine oxidase. In thioacetamide treated group, many fold increase in the activity level of serum marker enzymes suggesting FHF was observed that could be brought down significantly in rats receiving boron. Modulation and a correlation in the activity level of oxidant generating enzyme and lipid peroxidation as well as hepatic glutathione level was also observed in rats receiving thioacetamide. In the group receiving boron followed by thioacetamide, these changes could be minimized moderately. The activity level of the peroxide metabolizing enzymes and the tripeptide glutathione, which decreased following thioacetamide treatment were moderately elevated in the group receiving boron followed by thioacetamide. The data clearly shows that borax partly normalizes the liver and offsets the deleterious effects observed in FHF by modulating the oxidative stress parameters.

Liver necrosis and fulminant hepatic failure in rats: protection by oxyanionic form of tungsten.

The hepatic lesion produced as a result of oxidative stress is of wide occurrence. In the present study, the effect of tungsten on liver necrosis and fulminant hepatic failure (FHF) has been studied in rats treated with various compounds known to produce oxidative stress. Supplementation of animals with sodium tungstate for 7 weeks before the induction of liver injury by chemicals including thioacetamide (TAA), carbon tetrachloride (CCl(4)), or chloroform (CHCl(3)) could protect progression of hepatic injury. Various biochemical changes associated with liver damage and oxidative stress were measured. Hepatic malondialdehyde content, endogenous tripeptide, and reduced glutathione were measured as oxidative stress markers. The activity of xanthine oxidase, which generates reactive oxygen species (ROS) as a by-product, was also determined and found to be perturbed. Tungsten supplementation to rats caused a significant decrease in lipid peroxidation and lowered the levels of the biochemical markers of hepatic lesions produced by TAA, CCl(4) (CCl(4)), or CHCl(3). Tungsten could also cause an increase in the survival rate in rats receiving lethal doses of TAA, CCl(4), or CHCl(3). The protective effect of tungsten, however, is suggested to be limited to the conditions where the hepatic lesion is reported to be due to the generation of ROS. The progression of liver injury produced by the compounds causing oxidative stress without initiating the generation of free radicals such as bromobenzene (BB), or acetaminophen (AAP), could not be inhibited by tungsten. The possible mechanism explaining the role of oxyanionic form of tungsten in free radical-induced hepatic lesions is discussed.