Tryptophan metabolism in patients with pellagra: problem of vitamin B6 enzyme activity and feedback control of tryptophan pyrrolase enzyme

Open Access
Publisher Website
Google Scholar
Abstract
South African Bantu subjects with pellagra (from eating corn) were studied with the tryptophan load test, kynurenine load test, vitamin B6 therapy, or niacin therapy to determine the basic abnormality in metabolism in this disease. The low tryptophan and niacin content of the diet was reflected in the very low levels of tryptophan metabolites and niacin metabolites excreted in the basal urines. Elevated urinary levels of two or more tryptophan metabolites of the kynurenine pathway were observed in 16 of 22 subjects given an oral load of 2.0 g l-tryptophan. Kynurenine, hydroxykynurenine, kynurenic acid, and xanthurenic acid were the most commonly elevated components in the urine specimens. These abnormalities were corrected in most cases when pyridoxine was given to the subjects. Niacin therapy for 4 days reduced the excretion of kynurenine pathway metabolites in some patients maintained on a corn diet, suggesting that pyridine nucleotides of tissues had exerted some control of tryptophan pyrrolase activity as has been shown by others. To bypass alterations in tryptophan pyrrolase activity, a series of pellagrins was given oral doses of kynurenine without and with pyridoxine. Vitamin B6 therapy partially normalized the abnormal kynurenine metabolite levels observed in the urine of pellagra patients, after an l-kynurenine load test. N1-Methylnicotinamide and pyridone levels were low after the 2-g tryptophan load and the l-kynurenine load. Vitamin B6 improved the urinary levels of these components when given with the 2-g tryptophan load, but was not as effective when given with the l-kynurenine load. Quinolinic acid levels increased significantly when l-kynurenine or l-tryptophan was given. Vitamin B6 increased the urinary levels further when given with l-kynurenine but not with l-tryptophan. The leucine inhibition of NADP formation described by others would partially account for the increased urinary quinolinic acid seen after kynurenine administration. Pellagrins have three potential problems, which are a) depression of NADP synthesis by amino acid imbalance (high leucine diet); b) a lack of feedback control of the tryptophan pyrrolase enzyme by NADP; and c) subnormal vitamin B6 coenzyme levels.