Correlation of kynurenine excretion with liver tryptophan pyrrolase levels in disease and after hydrocortisone induction.

Abstract

In a large variety of apparently unrelated diseases, the major pathway of tryptophan metabolism, that which proceeds through kynurenine, has been observed to be abnormal. The deviation is a quantitative one: the urinary excretion of one or more normal metabolites is high. Attempts to explain this phenomenon have largely been restricted to hypotheses that assume a "metabolic block" in the catabolism of these metabolites, as exemplified by pyridoxine deficiency. However, it seems unlikely that the variety of conditions associated with the increased excretion of these tryptophan metabolites, e.g., Hodgkin's disease, rheumatoid arthritis, schizophrenia, porphyria, renal tuberculosis, and aplastic anemia, to mention only a few that are included in a recent review (1), would all be coupled specifically with pyridoxine deficiency. Being inducible by its specific substrate (6) and, through a different mechanism involving RNA synthesis (7), by glucocorticoids (8, 9), it has served as the model of mammalian adaptive enzymes and has drawn attention to the important physiological regulation of metabolism mediated by changes in the amounts of enzymes (10, 4). The quantitative study of tryptophan pyrrolase in human liver appeared to be necessary for approaching the causes that underlie the abnormal tryptophan metabolism in various diseases. MethodsThe hospitalized subjects with various diseases were all ambulatory and in no acute distress, with the indicated exception of those who were undergoing abdominal surgery. They were kept on a regular hospital diet and received no medications for at least 1 week before, and during, these studies. Unless otherwise indicated, no pa--tient was included who had been taking corticosteroids, sedatives, tranquilizers, or vitamin preparations for a prolonged period of time. The urinary excretion of kynurenine during the 24 hours after an oral dose of 2 g L-tryptophan was determined by the method of Tompsett (11).Specimens of human liver were obtained by Menghini needle biopsy by the standard percutaneous aspiration technique. When indicated, larger liver samples were obtained by excision from surgical patients during laparotomy. With these larger samples, a microassay suitable 1527

Comparison between tryptophan methoxyindole and kynurenine metabolic pathways in normal and preterm neonates and in neonates with acute fetal distress

“…This equilibrium is lost under conditions of stress (5,6,34,36), and the degree of deviation depends on both the type of stress experienced and the patient. Two types of neonatal stress, prematurity and fetal distress, were studied here.…”

Circadian periodicity of tryptophan metabolism

“…However this explanation would imply the extremely unlikely possibility that all tryptophan degradative enzymes distal to TP had a similar or identical rhythmic pattern. In this context Altman and Greengard (1) indicated that at times of elevated TP activity the kynurenine degradative enzymes, kynureninase, kynurenine hydroxylase, and kynurenine transaminase, become rate-limiting; While it is functionally possible to exceed the capacity of these enzymes to degrade kynurenine, the products of these enzymes as measured herein varied in the same diurnal fashion as did kynureCircadian Periodicity of Tryptophan Metabolism nine itself. The fact that the ratios of these metabolites were somewhat dissimilar may indeed suggest that enzymes subsequent to TP become ratelimiting during the period of maximal TP activity.…”

“…Recent studies in which liver biopsies were obtained showed that TP in humans could also be induced by pharmacologic quantities of adrenal glucocorticoids (1).…”

“…However the mechanisms underlying these defects have not been clearly established. In a recent publication Altman and Greengard (1) indicated that illness characterized by altered tryptophan metabolism could be associated with induction of the liver enzyme tryptophan pyrrolase (TP). This enzyme is the initial one in the kynurenine pathway and appears to regulate the rate of tryptophan metabolism through this pathway.…”

Biochemistry of Depression

“…In the past, liver biopsy was necessary to determine pyrrolase activity but recently an indirect method which is almost as effective has become available. After a small dose of L-tryptophan the excretion of kynurenine, a metabolite of tryptophan resulting from pyrrolase activity, is almost proportional to pyrrolase activity of biopsied liver material (1).…”