Formation of GSH-derivatives as a pathway for inactive intermediates in vinylidene chloride-treated rats.
The two conjugates, S-[N-(2-hydroxyethyl)carbamoylmethyl]glutathione (GSAAE), and its corresponding mercapturic derivative N-acetyl-S-[N-(2-hydroxyethyl)carbamoylmethyl]cysteine (NCySAAE) were administered to fasted Sprague-Dawley rats as putative metabolites of vinylidene chloride (VDC). Methylthioacetylaminoethanol (MAAE) was identified in the urine of GSAAE- or NCySAAE-treated rats (0.5-2.0 mmol/kg, i.p.), as well as in the urine of VDC-treated rats (0.5-2.0 mmol/kg, p.o.). The effects of VDC, GSAAE and NCySAAE on the kidney and liver were also examined using aspartate aminotransferase (ASAT). N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta 2-m) as urinary parameters of nephrotoxicity, and glutamate dehydrogenase (GLDH), sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALAT) as serum parameters of hepatotoxicity. Unlike treatment with VDC, treatment with both GSAAE and NCySAAE failed to cause kidney and liver toxicity. The results support the hypothesis that MAAE originates from the formation of GSAAE and further metabolization to NCySAAE, and that MAAE excretion does not reveal a pathway of reactive intermediates.
Cossec
B
B
Institut National de Recherche et de Sécurité, Vandoeuvre, France.
Cavelier
L
L
Moitessier-Bergé
N
N
Morel
G
G
de Ceaurriz
J
J
D000118:Acetylglucosaminidase / Q000187:drug effects; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004000:Dichloroethylenes / Q000633:toxicity*; D004983:Ethanolamines / Q000652:urine; D005969:Glutamate Dehydrogenase / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D007064:L-Iditol 2-Dehydrogenase / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D010088:Oxidoreductases / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000637:Transaminases / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000187:drug effects
D004000:Dichloroethylenes; D004983:Ethanolamines; C103739:N-acetyl-S-(N-(2-hydroxyethyl)carbamoylmethyl)cysteine; C103738:S-(N-(2-hydroxyethyl)carbamoylmethyl)glutathione; D001613:beta 2-Microglobulin; C029297:vinylidene chloride; C020773:methylthioacetylaminoethanol; D010088:Oxidoreductases; D007064:L-Iditol 2-Dehydrogenase; D005969:Glutamate Dehydrogenase; D000637:Transaminases; D000118:Acetylglucosaminidase; D005978:Glutathione; D003545:Cysteine