The role of glutathione and cysteine conjugates in the nephrotoxicity of o-xylene in rats.
Moderate nephrotoxicity was induced in male and female rats exposed to o-xylene for 4 h at atmospheric concentrations of approximately 3000 ppm. The xylene in vivo nephrotoxicity resulted in low enzyme leakage from the kidney into the urine. This low leakage was confirmed in 24-h urine by an increase in gamma-glutamyltranspeptidase (gammaGT), N-acetyl-beta-D-glucosaminidase (NAG) and alkaline phosphatase (ALP) activities. Compared to the control, both the 24-h urine output and the glucose excretion increased in male and female rats. These increases were probably a result of damage to the renal proximal tubules. The role of the metabolic pathway of glutathione in the emergence of the renal damage observed with o-xylene was investigated in rats. Recent studies indicate that the metabolic pathway of glutathione may be a bioactivation pathway, which is responsible for nephrotoxic effects with several drugs or chemicals. The renal toxicity of three synthesized o-xylene thio-conjugates was investigated in several groups of female rats. Administration of S-(o-methylbenzyl)glutathione (i.p., 1 mmol/kg), S-(o-methylbenzyl)cysteine (per os, 1 mmol/kg) or N-acetyl-S-(o-methylbenzyl)cysteine (i.p., 0.75 mmol/kg) to female rats did not induce renal toxicity, as monitored by urinary biochemical parameters (gammaGT, NAG, ALP, glucose). The data obtained suggest that the glutathione pathway would appear to be only detoxication, and probably does not contribute to the renal toxicity of o-xylene in female rats. Thus, either another metabolic pathway or other intermediate metabolites are probably involved in the nephrotoxic action of o-xylene.
Morel
G
G
Institut National de Recherche et de Sécurité, Vandoeuvre, France.
Bonnet
P
P
Cossec
B
B
Morel
S
S
Cour
C
C
Lambert
A M
AM
Roure
M B
MB
Brondeau
M T
MT
D000280:Administration, Inhalation; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D006029:Glycosuria / Q000209:etiology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000652:urine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014992:Xylenes / Q000633:toxicity*
C116309:S-(o-methylbenzyl)cysteine; C116310:S-(o-methylbenzyl)glutathione; D014992:Xylenes; D005978:Glutathione; D003545:Cysteine; C026114:2-xylene