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

Liver fluke infection (Fasciola hepatica) depresses the drug-metabolizing capacity of the hepatic mixed function oxidase (MFO) and glucuronosyltransferase (GT) enzyme systems, throughout a free radicals mediated lipid peroxidation process. Glutathione (GSH, CAS 70-18-8) administered chronically (100 mg/kg ip., once daily for 40 days) to experimentally infested rats from the onset to the maximal development of the infection (40th day), greatly reduced the damage to membrane lipids of the liver tissue (primary event of the disease), as judged by malonic dialdehyde (MDA) content (decreased by 80 %) and diene conjugation absorption (DELTAE 1 % value falls from 1.94 to 0.67). As a consequence, serum glutamate-oxaloacetate (GOT) and glutamate-pyruvate (GPT) transaminases levels, liver GSH and phospholipid (PL) contents, cytochrome P-450, NADPH-cytochrome-P-450 reductase and some typical cytochrome P-450-dependent activities (p-nitroanisole 0-demethylase, aniline hydroxylase, as well as UDP-glucuronosyltransferase (GT) activity, all markedly affected in the acute stage of the disease, tend to recover to the control values. The efficacy of GSH in preventing the impairment of the hepatic drug metabolizing capacity was also demonstrated by using as substrate the widely employed flukicidal agent nitroxinil (3-iodo-4-hydroxy-5-nitrobenzonitrile). The in vitro cytochrome P-450-dependent nitroxinil detoxification (reduction to 3-iodo-4-hydroxy-5-aminobenzonitrile), drastically impaired in infested animals (-80 %), is markedly restored (3-fold increase) in GSH-treated rats. After acute administration of nitroxinil (25 mg/kg s.c. the 96-h urinary elimination of the main metabolites of the drug (3-iodo-4-hydroxy-5-aminobenzonitrile, M1, and 3-iodo-4-hydroxy-5-acetylaminobenzonitrile, M2), greatly reduced in infested animals (-35/40 % vs. controls), is significantly increased (in the range of controls) in GSH-protected rats. These results evidence that GSH, acting as a potent antilipoperoxidative agent, is able to 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 nitroxinil.