EFFICACY OF GLUTATHIONE FOR TREATMENT OF FASCIOLIASIS - AN INVESTIGATION IN THE EXPERIMENTALLY INFESTED RAT

Liver fluke infection (Fasciola hepatica) depresses the drug-metaboliz ing capacity of the hepatic mixed function oxidase (MFO) and glucurono syltransferase (GT) enzyme systems, throughout a free radicals mediate d lipid peroxidation process. Glutathione (GSH, CAS 70-18-8) administe red chronically (100 mg/kg ip., once daily for 40 days) to experimenta lly infested rats from the onset to the maximal development of the inf ection (40th day), greatly reduced the damage to membrane lipids of th e liver tissue (primary event of the disease), as judged by malonic di aldehyde (MDA) content (decreased by 80 %) and diene conjugation absor ption (DELTAE 1 % value falls from 1.94 to 0.67). As a consequence, se rum glutamate-oxaloacetate (GOT) and glutamate-pyruvate (GPT) transami nases levels, liver GSH and phospholipid (PL) contents, cytochrome P-4 50, NADPH-cytochrome-P-450 reductase and some typical cytochrome P-450 -dependent activities (p-nitroanisole 0-demethylase, aniline hydroxyla se, as well as UDP-glucuronosyltransferase (GT) activity, all markedly affected in the acute stage of the disease, tend to recover to the co ntrol values. The efficacy of GSH in preventing the impairment of the hepatic drug metabolizing capacity was also demonstrated by using as s ubstrate the widely employed flukicidal agent nitroxinil (3-iodo-4-hyd roxy-5-nitrobenzonitrile). The in vitro cytochrome P-450-dependent nit roxinil detoxification (reduction to 3-iodo-4-hydroxy-5-aminobenzonitr ile), drastically impaired in infested animals (-80 %), is markedly re stored (3-fold increase) in GSH-treated rats. After acute administrati on of nitroxinil (25 mg/kg s.c. the 96-h urinary elimination of the ma in metabolites of the drug (3-iodo-4-hydroxy-5-aminobenzonitrile, M1, and 3-iodo-4-hydroxy-5-acetylaminobenzonitrile, M2), greatly reduced i n infested animals (-35/40 % vs. controls), is significantly increased (in the range of controls) in GSH-protected rats. These results evide nce that GSH, acting as a potent antilipoperoxidative agent, is able t o prevent the loss of the drug-metabolizing capacity of the liver cell in the course of fascioliasis even in the acute stage of the disease, thus shortening the persistence in the body of the flukicidal drug ni troxinil.