Effects of Bacterial Eni)otoxins on Metabolism

It was suggested in the most recent paper of this series (1) that protection by cortisone against the lethal effect of bacterial endotoxin is related to the ability of this and other glucocorticoids to induce de novo synthesis of certain liver enzymes (2-4). The injection of selected intermediates along the metabolic pathway initiated by the enzyme tryptophan pyrrolase increased survivorship following endotoxin poisoning, indicating that tryptophan pyrrolase plays a protective role in the response of mice to bacterial lipopolysaccharide. It was recognized that other inducible enzymes also might promote reactions of equal or greater importance to the intoxicated animal. One of the significant findings in support of the concept that enzyme induction is involved in an animal's response to endotoxin was the failure of cortisone to induce tryptophan pyrrolase in mice when it was injected 4 hours after administration of the LDs0 of endotoxin (1). Under the same conditions, cortisone is unable to increase the number of surviving mice. Apparently, therefore, endotoxin is able to block the synthesis of enzyme (protein) stimulated by cortisone. In agreement with the ability of endotoxin to prevent enzyme induction are observations (5) that two known inhibitors of protein synthesis, actinomycin D and ethionine, when administered in sublethal amounts, significantly potentiate endotoxin toxicity in mice. These inhibitors also eliminate the protective effect of cortisone against endotoxin lethality. The experiments described in this report extend these studies to include additional inhibitors of protein synthesis and correlate survival data with inducibility of tryptophan pyrrolase.