The ability of certain adrenocortical hormones to protect experimental animals against the lethal effects of lipopolysaccharides derived from Gramnegative bacteria is well established (14). The underlying basis for this protection has not been determined. Brooke et al. (5) recently reported for several adrenocorticoids a lack of correlation between their antllnflammatory properties and their ability to protect against endotoxins. It is perhaps a matter of faith that leads one to the view that all such hormonal capabilities (and of other substances with pharmacological actions as well) are ascribable to primary biochemical or metabolic effects. The problem becomes a matter of detecting the significant enzymic "needle" from among the mammalian "haystack" of enzymes. A number of enzymes may become altered by hormonal injections after a suflficient delay but most of these changes are probably secondary or adaptive rather than primary. A hopeful way out of this challenging situation is to find alternate ways of modifying an enzyme to see if by both methods a protective effect against endotoxins results.Such an approach to the problem of corticoid protection against endotoxin is made possible by the work of Knox and Auerbach (6) and Feigelson et al. (7). These investigators have shown that an injection of cortisone into rats is followed within about 4 hours by a significant increase in liver tryptophan pyrrolase. The enzyme also becomes more active following an injection of tryptophan, probably as a result of induced enzyme formation.Very briefly, tryptophan pyrrolase, with hematin as cofactor, oxidatively converts tryptophan into formyl kynurenine which, in turn, is further degradated into nicotinic acid. The ultimate metabolic fate of tryptophan v/a this pathway is the incorporation of nicotinamide into the di-and triphosphopyridine nucleotides (DPN and TPN), compounds of major significance in the energy release by organisms.
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