Enhanced sinusoidal glutathione efflux during endotoxin-induced oxidant stress in vivo.
Hepatic release of reduced glutathione (GSH) and its oxidation [glutathione disulfide (GSSG) formation] were investigated in male Fischer rats in vivo after administration of various doses (1-15 mg/kg) of endotoxin (Salmonella enteritidis). Endotoxin dose dependently enhanced basal plasma glutathione (9.64 +/- 0.80 microM) and GSSG (1.08 +/- 0.23 microM GSH equivalents) levels by up to 450 and 1,300%, respectively, 60 min after administration of the highest dose. Determination of arteriovenous differences of plasma glutathione and portal vein blood flow demonstrated an increase of basal sinusoidal glutathione efflux (18 nmol.min-1.g liver wt-1) by 300% 15 min after 5 mg/kg endotoxin. Activation of Kupffer cells by retinol enhanced endotoxin-induced release of GSH and its oxidation severalfold. Endotoxin enhanced plasma levels of catecholamines; however, only an epinephrine-induced not the endotoxin-induced stimulation of hepatic GSH efflux was inhibited by adrenergic blockers. Depletion of serum complement by cobra venom factor pretreatment completely abolished the endotoxin-induced increase of GSH release and enhanced GSSG formation. Zymosan-activated serum (source of C5a) increased GSSG formation and GSH release. It is concluded that endotoxin triggered an extracellular oxidant stress and an increased release of hepatic GSH indirectly through complement activation. Increased sinusoidal efflux of GSH and its extracellular oxidation may act as a local defense mechanism against the potentially deleterious effects of reactive oxygen generated by Kupffer cells during their physiological functions.
Jaeschke
H
H
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
D000818:Animals; D003165:Complement System Proteins / Q000502:physiology; D004731:Endotoxins / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism*; D019803:Glutathione Disulfide; D008099:Liver / Q000378:metabolism*; D008297:Male; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013565:Sympatholytics / Q000494:pharmacology
D004731:Endotoxins; D016877:Oxidants; D013565:Sympatholytics; D003165:Complement System Proteins; D005978:Glutathione; D019803:Glutathione Disulfide; D004837:Epinephrine