The mediated effect of endotoxin and lead upon hepatic metabolism.
A test was made of the possibility that gram-negative bacterial cell wall lipopolysaccharides acted directly on key glucoregulatory enzymes in rat liver cytosol to cause the characteristic hypoglycemia of severe endotoxemia. Fasted male rats were sensitized to endotoxin by the simultaneous intravenous injection of lead acetate. The minimum systemic dosage of endotoxin necessary to perturb the normal pattern of hepatic glycolytic intermediates was determined by serial testing with diminishing dosages of endotoxin. The hepatocyte concentration of endotoxin was then calculated from this minimum dosage by use of literature data on the fraction of endotoxin delivered to liver cells after a systemic intravenous injection of radiochromium labeled lipopolysaccharides. Accepting a molecular weight of 118,000 daltons for the smallest endotoxin monomer capable of evoking a physiologic response, the molar amount of endotoxin present in 1 gram of hepatocytes was readily calculated. The concentration of glucoregulatory enzymes in parenchymal cells was then estimated from other literature sources. It was found that the amount of endotoxin in the hepatocytes was insufficient to combine directly with even 1 per cent of the quantity of a single key glucoregulatory enzyme in liver parenchyma. Since a one to one stoichiometric reaction between endotoxin and enzyme could not occur in the liver cytosol, a direct interaction mechanism between agonist and biocatalyst can be ruled out. It is concluded that bacterial endotoxin must act on hepatic glucoregulation by an indirect mechanism presumably based upon the release and operation of mediators.
D000818:Animals; D050260:Carbohydrate Metabolism; D002860:Chromium Radioisotopes; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity*; D004926:Escherichia coli; D006019:Glycolysis; D007854:Lead / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009942:Organometallic Compounds; D051381:Rats; D011919:Rats, Inbred Strains
D002860:Chromium Radioisotopes; D004731:Endotoxins; D008070:Lipopolysaccharides; D009942:Organometallic Compounds; D007854:Lead; C008261:lead acetate