Modulation of benzoquinone-induced cytotoxicity by diethyldithiocarbamate in isolated hepatocytes.
The copper-chelating thiol drug diethyldithiocarbamate protected isolated hepatocytes from benzoquinone-induced alkylation cytotoxicity by reacting with benzoquinone and forming a conjugate which was identified by fast atom bombardment mass spectrometry as 2-(diethyldithiocarbamate-S-yl) hydroquinone. In contrast to benzoquinone, the conjugate was not cytotoxic to isolated hepatocytes. The thiol reductant dithiothreitol had no effect on benzoquinone-induced alkylation cytotoxicity. However, inactivation of catalase in the hepatocytes with azide and addition of the reducing agent ascorbate markedly enhanced the cytotoxicity of the conjugate but did not affect benzoquinone-induced cytotoxicity. Furthermore, inactivation of glutathione reductase and catalase in hepatocytes greatly enhanced the cytotoxicity of the conjugate and caused oxidation of GSH to GSSG. The conjugate also stimulated cyanide-resistant respiration, which suggests that the conjugate undergoes futile redox cycling resulting in the formation of hydrogen peroxide which causes cytotoxicity in isolated hepatocytes only if the peroxide detoxifying enzymes are inactivated. Diethyldithiocarbamate does, however, protect uncompromised isolated hepatocytes from benzoquinone cytotoxicity by conjugating benzoquinone, thereby preventing the electrophile from alkylating essential macromolecules. Diethyldithiocarbamate therefore changed the initiating cytotoxic mechanism of benzoquinone from alkylation to oxidative stress, which was less toxic.
Lauriault
V V
VV
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
McGirr
L G
LG
Wong
W W
WW
O'Brien
P J
PJ
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D002374:Catalase / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004050:Ditiocarb / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D007700:Kinetics; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D016339:Spectrometry, Mass, Fast Atom Bombardment
D016227:Benzoquinones; C004532:quinone; D004050:Ditiocarb; D002374:Catalase; D001205:Ascorbic Acid