Effects of diethyl maleate on phenyl-hydroquinone-induced cytotoxicity in isolated rat hepatocytes.
1. The effects of diethyl maleate (DEM) on the cytotoxicity of phenyl-hydroquinone (PHQ) and other hydroquinones were studied in freshly isolated rat hepatocytes. 2. Addition of PHQ (0.5 or 0.75 mM) to hepatocytes resulted in dose-dependent cell death accompanied by the abrupt depletion of both GSH and protein thiols and the accumulation of phenyl-benzoquinone (PBQ). 3. Pretreatment with DEM (1.25 mM), which causes an abrupt depletion of cellular GSH in hepatocytes, delayed the onset of PHQ-induced cytotoxicity. The delay correlated with inhibition of PBQ formation. 4. Although the pH of the cell suspension was increased slightly (mean pH 0.18) by incubation under carbogen flow, the addition of DEM to the cell suspension inhibited both the increase in pH and the formation of PBQ from PHQ. 5. In hepatocyte suspensions without DEM, PHQ cytotoxicity was dependent on pH, and toxicity was associated with oxidation of PHQ and accumulation of PBQ. 6. Among other hydroquinones (0.5 mM), tert-butyl-hydroquinone-induced cytotoxicity was decreased by DEM (1.25 mM), but DEM did not affect the cytotoxicity of 2,5-di(tert-butyl)-1,4-benzohydroquinone. 7. PHQ-induced cytotoxicity correlated with the accumulation of PBQ in the cell, and the inhibition of PHQ-induced cytotoxicity by DEM correlated with pH-dependent changes in PBQ formation.
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Y
Y
Nakagawa
S
S
Tayama
G
G
Moore
P
P
Moldéus
D000818:Animals; D001713:Biphenyl Compounds / Q000633:toxicity*; D002245:Carbon Dioxide / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006873:Hydroquinones / Q000633:toxicity*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000378:metabolism
D001713:Biphenyl Compounds; D006873:Hydroquinones; D008298:Maleates; D011506:Proteins; D013438:Sulfhydryl Compounds; D002245:Carbon Dioxide; C011700:carbogen; C014476:diethyl maleate; D005978:Glutathione; C066330:phenylhydroquinone; D010100:Oxygen