Inhibition of biliary taurocholate excretion during menadione metabolism in perfused rat liver.
In perfused rat liver menadione elicits substantial oxidation in both the NADPH and GSH redox systems. Biliary excretion of GSSG is increased several-fold. Menadione derivatives appear in the bile predominantly as the menadione-S-glutathione conjugate, thiodione (60%), or as conjugates derived therefrom (17%). About 10% appear as menadione glucuronides. The excretion of taurocholate into bile is strongly inhibited upon menadione infusion. The inhibition of taurocholate excretion is small in livers with a low content of Se-GSH-peroxidase and in glutathione-depleted livers. In these livers intracellular GSSG and biliary GSSG release remain at low values, although menadione still imposes oxidative stress as indicated by an oxidation of intracellular NADPH. Under anoxic conditions menadione has little influence on both the NADPH and GSH redox systems and also on biliary taurocholate excretion. The amount of thiodione released into bile is similar to that found under normoxia, whereas the amount of glucuronidated products almost doubled. We conclude (a) that intracellular formation of GSSG by menadione occurs via the generation of hydrogen peroxide; (b) that the inhibition of biliary taurocholate excretion by menadione is related to the increased formation of glutathione disulfide; and (c) that menadione derivatives show little, if any, contribution to the inhibition of taurocholate excretion.
Akerboom
T
T
Institut für Physiologische Chemie I, Universität Düsseldorf, Federal Republic of Germany.
Bultmann
T
T
Sies
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D009249:NADP / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000172:deficiency; D013656:Taurocholic Acid / Q000378:metabolism*; D014812:Vitamin K / Q000378:metabolism / Q000494:pharmacology*
D007659:Ketones; D014812:Vitamin K; D009249:NADP; D013656:Taurocholic Acid; C018637:phorone; D000255:Adenosine Triphosphate; D005978:Glutathione; D012643:Selenium