Enalapril cytotoxicity in primary cultures of rat hepatocytes. II. Role of glutathione.
The cytotoxicity of enalapril maleate (EN) in primary cultures of rat hepatocytes, at concentrations of 0.5 mM or greater, was measured by the release of lactate dehydrogenase (LDH) into the culture medium. Pretreatment of the hepatocytes with L-buthionine-(S,R)-sulfoximine (BSO) and diethyl maleate (DEM) potentiated the toxicity whereas N-acetyl-L-cysteine (NAC) provided protection. EN produced a dose-dependent reduction in intracellular glutathione (GSH) concentration. This was an early effect, apparent after only 1 h of exposure to the drug, whereas loss of cell viability occurred after 6-18 h. These results suggest that the mechanism of EN cytotoxicity involves a GSH-dependent detoxification pathway.
Jurima-Romet
M
M
Biochemical Toxicology Section, Health and Welfare, Canada, Ottawa.
Huang
H S
HS
Paul
C J
CJ
Thomas
B H
BH
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004656:Enalapril / Q000633:toxicity*; D005978:Glutathione / Q000502:physiology*; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D000963:Antimetabolites; D008298:Maleates; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004656:Enalapril; D007770:L-Lactate Dehydrogenase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; C014476:diethyl maleate; D005978:Glutathione; D000111:Acetylcysteine