Comparison of the effects of redox cycling and arylating quinones on hepatobiliary function and glutathione homeostasis in rat hepatocyte couplets.
Menadione (2-methyl-1,4-naphthoquinone, a redox cycling and arylating quinone; 5-100 microM) inhibited the canalicular vacuolar accumulation (CVA) of a fluorescent bile acid, cholyl-lysyl-fluorescein (CLF), in rat hepatocyte couplets. This was associated with depletion of reduced glutathione and accumulation of oxidized glutathione, the latter indicating that the concentrations of menadione used were able to induce oxidative stress. There was no associated cytotoxicity as indicated by ATP content. Treatment of couplets with the redox cycling quinone 2,3-dimethoxy-1,4-naphthoquinone (up to 100 microM) had relatively little effect on CVA, suggesting that the magnitude of reactive oxygen formation induced by this compound was insufficient to disrupt canalicular integrity. In comparison, the arylation of protein thiol groups by p-benzoquinone (up to 100 microM) proved to be more potent in inhibiting canalicular vacuolar accumulation. The predominant mechanism of menadione-induced inhibition of couplet hepatobiliary function is therefore more likely to involve the arylation of critical thiol groups (such as those in the F-actin cytoskeleton) rather than their oxidation. The oxidative effects of menadione could, however, potentiate the deleterious effects induced by arylation, such as by reduced glutathione depletion.
Stone
V
V
School of Biochemistry, University of Birmingham, Edgbaston, United Kingdom.
Coleman
R
R
Chipman
J K
JK
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D001659:Biliary Tract / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects; D002469:Cell Separation; D005978:Glutathione / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology
D016227:Benzoquinones; D009285:Naphthoquinones; D014812:Vitamin K; C004532:quinone; C063002:2,3-dimethoxy-1,4-naphthoquinone; D000255:Adenosine Triphosphate; D005978:Glutathione