Inhibition of Inducible Liver Enzymes by Endotoxin and Actinomycin D

Abstract

Inhibition of inducible liver enzymes by endotoxin and actinomycin D. J. Bacteriol. 92:107-115. 1966.-Bacterial endotoxin at the LD50 level lowers liver tryptophan pyrrolase in mice, it prevents for 16 to 20 hr the induction of the enzyme by a concurrent injection of cortisone, it lowers significantly but does not prevent substrate induction, and it reduces the enzymatic activity promptly and significantly when administered during the course of hormonal induction. The LD50 amount of actinomycin D has a similar effect on tryptophan pyrrolase, except that its inhibition of induction by cortisone persists for a longer period of time. Endotoxin in the intact mouse induces tyrosine-a-ketoglutarate transaminase almost as well as cortisone, but not in the adrenalectomized animal, a fact that suggests induction of this enzyme is due to release of endogenous adrenal hormones. Actinomycin D, on the other hand, has an effect on this transaminase similar to that on tryptophan pyrrolase. The site of action of endotoxin and actinomycin D would appear to be similar for one of the two enzymes studied and different for the other, a relationship that requires a specificity difficult to imagine for a material as complex as endotoxin.

Enzyme Activities of the Livers of Mice Infected with Salmonella typhimurium

“…The investigation of changes in host enzyme activity after infection with S. typhimurium did not confirm prior studies on TO which showed an inhibition of this enzyme after injection of endotoxin (3,4). But the observed increases in TAT and PK are compatible with reported data (5,17).…”

“…The increase in activity of TAT during infection with S. typhimurium is consistent with published work on the effect of endotoxin on this enzyme (5). The increase in PK activity observed during infection is compatible with other work from our laboratory which shows an increase in PK activity after endotoxin injection (17).…”

“…Rapoport et al (15) have shown that induction of TO occurs early in the course of pneumococcal infection but returns to normal levels 1 day after infection. Berry et al (5) demonstrated that the activity of tyrosine aminotransferase (TAT) increases and suggested that the associated loss of glycogen in endotoxininjected animals might be related to inability of these animals to utilize glyconeogenic intermediates. Snyder et al (17) associated the increased activity of pyruvate kinase (PK) in endotoxininjected animals with the depletion of liver glycogen.…”

Study of Inhibition of Induction of Phosphoenolpyruvate Carboxykinase by Endotoxin with Radial Immunodiffusion

“…Endotoxin inhibits PEPCK, therefore, in a fashion similar to that of actinomycin D, but different from puromycin. The similarity of action of endotoxin and actinomcyin D on the induction of hepatic enzymes was first pointed out by Berry et al (1). It was reported by these investigators that actinomycin D and the bacterial poison yielded identical results in inhibiting the induction of the enzyme tryptophan oxygenase in animals that received 5 mg of cortisone acetate.…”

Inhibition of Hepatic Enzyme Induction as a Sensitive Assay for Endotoxin

“…The hormonal induction of two enzymes, tryptophan oxygenase and phosphoenolpyruvate carboxykinase, is strongly inhibited by endotoxin, whereas the third enzyme, tyrosine-a-ketoglutarate transaminase, is not inhibited. In intact mice, this enzyme is induced by endotoxin to approximately the same degree as it is by hormone, whereas only a limited but statistically significant induction occurs in adrenalectomized mice (5). The contrast in response of these three enzymes establishes the fact that endotoxin is not exerting its anti-inductive effect through general hepatotoxicity but, on the other hand, appears to have a selective action on certain enzymes.…”