THE ROLE OF GLUTATHIONE CONJUGATION IN THE DEVELOPMENT OF KIDNEY TUMORS IN RATS EXPOSED TO TRICHLOROETHYLENE

Trichloroethylene is metabolised to a very minor extent (<0.01% of the dose) by conjugation with glutathione, a metabolic pathway which lead s to the formation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a bacte rial mutagen and nephrotoxin activated by the renal enzyme beta-lyase. The role of this metabolic pathway in the development of the nephroto xicity and subsequent tumour formation seen in rats exposed to trichlo roethylene has been evaluated. The pathway has been assessed quantitat ively in vivo in rats, and in rats, mice and humans in vitro. Trichlor oethylene was found to be a very weak nephrotoxin. There was no eviden ce of morphological change in the kidneys and only small increases in biochemical markers of kidney damage in rats dosed with 2000 mg/kg tri chloroethylene by gavage for 42 days. N-acetyl-S-(1,2-dichlorovinyl)-L -cysteine was detected in the urine of rats dosed with 500 and 2000 mg /kg trichloroethylene for up to 10 days at levels equivalent to 0.001- 0.008% of the dose. In vitro, the rate of conjugation of trichloroethy lene with glutathione in the liver was higher in the mouse, 2.5 pmol/m in per mg protein, than the rat. 1.6 pmol/min per mg protein, and in h uman liver the rates were extremely low, 0.02-0.37 pmol/min per mg pro tein. Comparisons of the metabolism of DCVC by renal beta-lyase and N- acetyl transferase showed that metabolism by N-acetyl transferase was two orders of magnitude greater than that by beta-lyase and that beta- lyase activity in rat kidney was ii-fold greater than that in human ki dney. When the nephrotoxicity of DCVC was compared in rats and mice, t he mouse was found to be 5-10 fold more sensitive than the rat. The no effect level in the rat was 10 mg/kg, a dose which is three orders of magnitude higher than the amount of DCVC formed from trichloroethylen e in vivo. The lack of correlation between metabolism by this pathway and the rat specific tumours, together with questions concerning the p otency of DCVC at the levels formed from trichloroethylene, suggests t hat DCVC may not be involved in the renal toxicity and subsequent tumo ur development seen in rats and that further evaluation of the mechani sm(s) involved in the nephrotoxic response is warranted. (C) 1997 Else vier Science Ireland Ltd.