Pyridoxine deficiency xanthurenic acid, excretion

Tryptophan metabolism was investigated in neurological diseases (V5, Cl) in which the xanthurenic acid excretion was measured after ingestion of L-tryptophan (100 mg/kg). The greater amounts of xanthurenic acid excreted by certain patients suggested an alteration of tryptophan metabolism, probably related to pyridoxine deficiency. 

Xanthurenic acid excretion was followed in a group of 20 patients with diflFerent forms of anemia after a 10-g load of DL-tryptophan (R2). Abnormal increasing of urinary xanthurenic acid was considered by Rade-maker and Verloop an early diagnostic signal of a pyridoxine deficiency. A case of hypochromic anemia, unreactive to any therapy but pyridoxine, showed a normal excretion of xanthurenic acid. On the contrary, an increase on excretion of xanthurenic acid was observed in some iron-deficiency anemia patients whose anemia was not Bg-dependent (R2). 

Wohl et al. (W15) determined the occurrence of pyridoxine deficiency in 14 patients with hyperthyroidism and in 14 control euthyroid patients by loading with 10 g DL-tryptophan. Urinary xanthurenic acid excretion following the tryptophan dose was significantly greater in hyperthyroid patients than in controls. Mean xanthurenic acid excretion after pyridoxine administration was not significantly different in the two groups. It is suggested that it is not unreasonable to state that in hyperthyroidism the availability of pyridoxine is limited. 

Increased xanthurenic acid excretion after 10 g DL-tryptophan was demonstrated by Lerner et al. (L3) in 3 of 5 patients with rum fits. This metabolic defect was corrected by pyridoxine administration, as observed in a second tryptophan load test. Using the same xanthurenic acid test, significant vitamin Ba deficiency was not observed in patients with alcoholism and associated epilepsy, acute and chronic alcoholism, cirrhosis, acute hallucinosis-tremulousness, acute peripheral neuropathy, Wemicke-Korsakoff syndrome, and nonalcoholic, healthy individuals. It is postulated that pyridoxine deficiency is etiologically related to rum fits (L3). 

Sudakova and Ryvkin (S9) studied 52 patients of different ages with active rheumatism and determined their pyridoxine deficiency through the degree of disturbed tryptophan metabolism in the form of increased rates of xanthurenic acid excretion in urine. After a load of tryptophan the concentration of xanthurenic acid in urine of 40 patients rose to higher levels, in some cases as high as 300 mg, with a total average of 97 mg. Urinary xanthurenuria remained normal in only 9 patients... 

W12. Williams, H. L., and Wiegand, R. G., Xanthurenic acid excretion and possible pyridoxine deficiency produced by isonicotinic acid hydrazide and other con-vulsivant hydrazides. /. Pharmacol. Exptl. Therap. 128, 344-348 (1960). 

It was quickly established by many techniques (381, 430, 782, 817, 957, and review 170) that the conversion of tryptophan to nicotinic acid occurred in body tissues and was not due (except perhaps in part in exceptional circumstances cf. 170) to intestinal bacteria. Moreover nutritional studies showed that kynurenine was probably also a precursor of nicotinic acid (457) and that kynurenine and xanthurenic acid excretion were increased in pyridoxine deficiency (21). 

Quite recently Weber and Wiss (W8) studied the influence of vitamin Be depletion on various pyridoxal phosphate enzymes and found that rat liver kynureninase is much more affected by vitamin Be deficiency than kynurenine transaminase. In fact liver kynureninase of rats on a Be-deficient diet fell to 17%, whereas kynurenine transaminase was about 58% of the original activity after the same period. The different behavior of these two enzymes offers a way of studying closely the mechanism of the increased excretion of xanthurenic acid in pyridoxine... 

Weller and Fichtenbaum (WIO) followed the urinary excretion of xanthurenic acid in 48 arteriosclerotic patients after an oral dose of 10 g DL-tryptophan. On the basis of urinary xanthurenic acid above the range of normal controls, 29% of these patients showed a deficiency of vitamin Bg. Using the same criterion, pyridoxine deficiency was found in 60% of diabetic patients with arteriosclerotic complications. 

The disappearance of xanthurenic acid after pyridoxine dierapy suggested the possibility of a latent Be deficiency (Dl). Dahler-Vollen-weider (D2) screened 159 children in respect to the urinary picture of tryptophan metabolites and found an abnormal excretion of xanthurenic acid in 17, whereas 142 fell within normal limits after tryptophan loading. There seems to be an increased rate of excretion widi age. In the newborn the excretion was the lowest while the maximal values were found in the age group 10-16 years. During periods of rapid growth there was a high excretion rate of xanthurenic acid, which was not appreciably affected by daily oral administration of 100 mg pyridoxine. 

Increased excretion of xanthurenic acid was found (H7) in 13 cases of infantile spasm as compared with a control group of healthy infants, before and ter tryptophan loadings. This finding is interpreted as a sign of relative vitamin Be deficiency in tissue concerned with tryptophan metabolism caused by an increased demand for pyridoxine as a co-enzyme in the brain tissue. In most cases the disturbed tryptophan metabolism should have no direct relation to the cerebral symptoms, as these were not relieved by parenteral administration of high doses of vitamin Be. 

Wohl et (d. (W15) found that 4 diabetic patients excreted, before and after tryptophan loading, low levels of xanthurenic acid and that this is not modified by administration of pyridoxine or by a second test with 10 g DL-tryptophan. Kojecky and Telupinova (Kll) also found no increase in xanthurenic acid and 3-hydroxykynurenine excretion in diabetic patients loaded with 100 mg/kg of DL-tryptophan, whereas increased amounts of kynurenine were observed in tihe same patients. By determining urinary pyridoxine after a 1-g vitamin Be load and urinary xanthurenic acid after a 10-g tryptophan load, Lebon et al. LI) demonstrated pyridoxine deficiency in about half of 144 diabetic patients. This defect is more frequent in patients with juvenile diabetes and is curable by treatment with 0.5-1 g pyridoxine daily. 

Faber et al. (FI) studied the effects of induced pyridoxine and pantothenic acid deficiency, obtained by use of a semisynthetic formula and deoxypyridoxine and co-methyl pantothenic acid supplements for six weeks, by determining in 5 men nitrogen retention and the urinary excretions of xanthurenic and oxalic acids during deficiency and recovery. They postulated that tissue catabolism releases suflBcient pyri-doxine to partially metabolize a tryptophan load, after which the amounts of urinary oxalic acid were sharply increased for 1-2 days. 

Another disease of prominent dermatological interest is pellagra, in which pyridoxine deficiency seems to represent one of the pathogenetic factors even though of less importance than the fundamental niacin deficiency. For this reason Csermely and Zardi (G13) examined 12 patients with this disease in an attempt to demonstrate a pyridoxine deficiency by determining xanthurenic acid after loading wiA L-tryptophan (100 mg/kg). The results obtained (C13) show that an abnormal excretion of xanthurenic acid occurred in 5 of 12 patients. Furthermore, the clinical picture of the disease does not differ in patients with normal or abnormal xanthurenic acid output. These data provide no definite information in regard to this disease, in which more than one metabolite would have to be measured. 

G9. Glazer, H. S., Mueller, J. F., Thompson, C., Hawkins, V. R., and Vilter, R. W., A study of urinary excretion of xanthurenic acid and other tryptophan metabolites in human beings with pyridoxine deficiency induced by desoxypyridoxine. Arch. Bio-chem. Biophys. 33, 243-251 (1951). 

Reference has already been made to the abnormally high excretion of kynurenine and xanthurenic acid in pyridoxine deficiency. This was confirmed by many workers (e.g., 372, 599, 620, 674, 698, 732), and the reason for it became evident from enzymic experiments. 

Rose [305] reported the excretion of grossly increased amounts of xanthurenic acid in the urine of women taking combination products. A similar increase in tryptophan metabolites occurs in pregnancy and has been interpreted as indicating pyridoxine deficiency [306]. Dewhurst [307] subsequently postulated a causal connection between dysfunction of trytophan metabolism and certain types of depression. Winston [308] developed the concept further by suggesting that depression from oral contraceptive medication be treated with pyridoxine. Price and Toseland [309] have proposed routine inclusion of pyridoxine in oral contraceptive preparations. Developments will be awaited with interest. 

Xanthurenic acid was isolated from urine by Musajo in 1935 and shown to be 4,8-dihydroxyquinoline-2-carboxylic acid. Because of its 8-hydroxyquinoline structure it forms colored chelates with metal ions and, in particular, gives an intense green color with ferric salts. Xanthurenic acid is only excreted in pyridoxine deficiency, as was discovered by Lepkovsky and co-workers. It is found only in pyridoxine-defi-cient animals fed L-tryptophan or kynurenine. Addition of pyridoxine or the elimination of tryptophan from the diet causes it to disappear from the urine. ... 

The increased excretion of kynurenic and xanthurenic acids observed in pyridoxine deficiency is probably due to the preferential combination of the pyridoxal phosphate coenzyme with the transaminase. By preventing the loss of the side chain, as a result of a decreased activity of kynureninase in pyridoxine deficiency, cyclization is favored leading to increased formation of the two acids above. 

Pyridoxine deficiency has been induced by administration of desoxy-pyridoxine to adults receiving a diet low in B complex vitamins. Seborrheic skin lesions developed about the eyes, nose, and mouth, and cheilosis, glossitis, and stomatitis were observed. Although these findings resemble those commonly seen in riboflavin and niacin deficiency, healing was dependent on administration of pyridoxine. The deficient subjects excreted large amounts of xanthurenic acid in the urine after a test dose of tryptophan, but ability to convert tryptophan to niacin was unimpaired. 

This is the excretion product of 3-hydroxykynurenic acid, an intermediate in the conversion of tryptophan to nicotinic acid. Pyridoxal phosphate is required as a cofactor for the enzyme, kynureninase, which catalyses the conversion of 3-hydroxykynurenic acid to 3-hydroxyanthrinilic acid. In patients with pyridoxine deficiency, 3-hydroxykynurenic acid accumulates and is excreted in the urine as xanthurenic acid. Xanthurenic acid can therefore be measured in urine (especially after giving an oral typtophan load) in order to detect pyridoxine deficiency. 

Vitamin deficiency may produce seborrhea-like symptoms. In addition, tryptophan catabolism is disturbed kynurenine, 3-hydroxy-kynurenine, and xanthurenic acid appear in urine. Excess pyridoxine is oxidized to pyridoxinic acid (like pyridoxal, but with a carboxyl in place of the aldehyde group) and excreted. 

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