Induced histidine decarboxylase in endotoxic shock: identification of the enzyme in rat liver and influence of its inhibitors on survival parameters.
The hypothesis of a causal relationship between a progressive and unrestrained increase of tissue histamine formation by activation of an inducible histidine decarboxylase (HDC) and lethality in endotoxic shock (Schayer's 'induced histamine concept') was tested in a standardized rat endotoxic shock model. Initial enzyme identification studies in the rat shock liver (8 hrs after endotoxin challenge) clearly demonstrate that the 'induced' histidine decarboxylase is an acid (specific) HDC. The succeeding randomized, controlled study with appropriate inhibitors of the enzyme, alpha-methyl-histidine (competitive inhibitor) and alpha-fluoromethyl-histidine (irreversible inhibitor) using doses of 2, 20 or 100 mg/kg showed no significant effect on the survival rate of rats in endotoxin shock. The survival rate of the non-treated endotoxin control group (NaCl) was 25%; all methylprednisolone treated rats (50 mg/kg) survived. Thus, the 'induced' histamine is not a predominant factor (necessary or sufficient determinant) for the lethal outcome in rat endotoxic shock. The protective effect of MP is not predominantly due to the inhibition of the 'induced' histidine decarboxylase. The use of HDC-inhibitors as the appropriate instruments for evaluation of the significance of this mechanism is discussed.
D000818:Animals; D002262:Carboxy-Lyases / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D006632:Histamine / Q000096:biosynthesis; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D008762:Methylhistidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012772:Shock, Septic / Q000201:enzymology* / Q000401:mortality
D008762:Methylhistidines; C046181:alpha-methylhistidine; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D002262:Carboxy-Lyases; D006640:Histidine Decarboxylase