© 1996 Oxford University Press
research-article |
Biotransformation of the Fungicide Chlorthalonil by Glutathione Conjugation
Department of Toxicology, University of Wünburg Versbacher Strasse 9 Würzburg 97078, Federal Republic of Germany
Received February 23, 1996; accepted May 14, 1996
The biotransformation of the nephrotoxic fungicide chlorthalonil (2,4,5,6-tetrachloroisophthalonitril) has been studied in the rat and in rat liver subcellular fractions. In rat liver cytosol, chlorthalonil was rapidly transformed to 4,6-bis(glutathion-S-yl)-2,5-dichloroisophthalonitril in the presence of glutathione in a reaction catalysed by glutathione S-transferases. 4-{Glutathion-S-yl)-2,5,6-trichloroisiphthalonitril was observed as an intermediate in the glutathione-dependent biotransformation of chlorthalonil. In the bile of rats dosed with chlorthalonil (0.18 mmol/kg, orally) 4,6-bis(glutathion-S-yl)-2,5-dichloroisophthalonitril was recovered as a minor metabolite. In rats, chlorthalonil was transformed to 4,6-bis(N-acetyl-cystein-S-yl)2,5-dichloroisophthalonitril. This metabolite was excreted in small amounts in the urine of rats dosed orally with chlorthalonil (0.66 and 2.64 mmol/kg). In all experiments, a major part of the dose was recovered as unchanged chlorthalonil in feces. Oral administration of chlorthalonil (0.66 and 2.64 mmol/kg) resulted in a slight increase in the urinary excretion of 
-glutamyltranspeptidase, indicative of nephrotoxicity. Other parameters indicative for renal proximal tubular damage (urinary glucose and protein excretion) were not changed by acute chlorthalonil administration. Very minor renal lesions were observed in chlorthalonil-dosed animals by histopathological examination.