The role of glutathione conjugation in the development of kidney tumours 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 leads to the formation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a bacterial mutagen and nephrotoxin activated by the renal enzyme beta-lyase. The role of this metabolic pathway in the development of the nephrotoxicity and subsequent tumour formation seen in rats exposed to trichloroethylene has been evaluated. The pathway has been assessed quantitatively in vivo in rats, and in rats, mice and humans in vitro. Trichloroethylene was found to be a very weak nephrotoxin. There was no evidence of morphological change in the kidneys and only small increases in biochemical markers of kidney damage in rats dosed with 2000 mg/kg trichloroethylene 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 trichloroethylene with glutathione in the liver was higher in the mouse, 2.5 pmol/min per mg protein, than the rat, 1.6 pmol/min per mg protein, and in human liver the rates were extremely low, 0.02-0.37 pmol/min per mg protein. 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 11-fold greater than that in human kidney. When the nephrotoxicity of DCVC was compared in rats and mice, the 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 trichloroethylene in vivo. The lack of correlation between metabolism by this pathway and the rat specific tumours, together with questions concerning the potency of DCVC at the levels formed from trichloroethylene, suggests that DCVC may not be involved in the renal toxicity and subsequent tumour development seen in rats and that further evaluation of the mechanism(s) involved in the nephrotoxic response is warranted.
Green
T
T
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Dow
J
J
Ellis
M K
MK
Foster
J R
JR
Odum
J
J
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D013437:Carbon-Sulfur Lyases; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D007668:Kidney / Q000201:enzymology; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D007700:Kinetics; D008190:Lyases / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; C041464:S-(1,2-dichlorovinyl)glutathione; D001191:Arylamine N-Acetyltransferase; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D005978:Glutathione; D003545:Cysteine