Pyridoxine urinary excretion

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. 

Harris et al. (H4) reported a case of an adult patient with hematological abnormalities unresponsive to the usual hematopoietic agents and characterized by a hypochromic anemia, leucocytosis, high serum iron, and high percent iron-binding protein saturation. Measurements of the urinary excretion of kynurenine, kynurenic acid, acetylkynurenine, xanthurenic acid, o-aminohippuric acid before and after an oral dose of 4 g L-tryptophan indicated abnormalities of tryptophan metabolism. This alteration was partially normalized on a 1-mg pyridoxine dose and completely normalized at the 10-mg level. Also the clinical and laboratory abnormalities disappeared and hematological remission followed the pyridoxine administration. 

Auricchio et al. (A12) analyzed the excretory pattern of 6 children with leukemia and 2 with Hodgkin s disease. No definite relationship could be observed between the disease and the abnormally elevated amounts of tryptophan metabolites. After niacin therapy the urinary excretion of kynurenines and kynurenic and xanthurenic acids was normalized in one case of Hodgkin s disease and in one leukemic subject after pyridoxine administration. 

Despite normal plasma pyridoxal 5-phosphate values, the urinary excretion of xanthurenic acid was found abnormally elevated in 3 epileptic children with disturbed tryptophan metabolism (HO). Administration of pyridoxine restored xanthurenuria to normal and raised plasma pyridoxal 5-phosphate levels. 

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. 

These studies indicate an intimate relation between the magnesium level of the diet and the pyridoxine requirement. It is suggested (A6) that, insofar as growth and urinary excretion of citrates, oxalates, and xanthurenic acid are concerned, high levels of magnesium appear to have a sparing effect on very low dietary levels of pyridoxine. 

For the authors (PIO) the simplest explanation of the data on tryptophan metabolism in these 3 patients would be as follows in scleroderma (acrosclerosis) there was an abnormal urinary excretion of kynurenine and its metabolites after oral ingestion of tryptophan. The administration of pyridoxine or pyridoxine plus nicotinamide partially corrected the metabolic abnormality. The efficacy of pyridoxine plus Na2EDTA could be explained on the basis of a decrease in tissue calcium and zinc (and possibly other cations), enabling the metal ions, normally functioning with pyridoxal phosphate, as magnesium ions, to be utilized more advantageously. 

In subsequent studies (K7), 9 members of 3 different families were loaded with 10 g OL-tryptophan which resulted in a 10-20-fold increase in the 24-hour urinary excretion of kynurenine, 3-hydroxykynurenine, and xanthurenic acid. It appears to be a genetically conditioned disturbance, with dominant inheritance, involving metabolic reactions dependent upon pyridoxine. In most subjects the urinary changes after tryptophan loading could be corrected by vitamin Be therapy. The following diseases were found in this order of frequency in these subjects and their families bronchial asthma, chronic urticaria, anemia, diabetes, arices, and crural ulcers. Knapp s (K7) conclusion is that these disorders may be partially attributable to metabolic disturbances. 

Peripheral neuropathy has been observed as a complication in tuberculosis therapy with isonicotinic acid hydrazide (isoniazid), especially when large doses have been employed (B14). This complication of isoniazid therapy has been largely eliminated by simultaneous administration of pyridoxine. These observations have prompted studies on the urinary excretion of xanthurenic acid as an index of the antipyridoxine activity of isoniazid. The excretion of an excess of vitamin Be as such... 

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). 

As will be discussed in this section, some women taking OCAs have increased urinary excretion of tryptophan metabolites. The pattern of excretion of these metabolites resembles that found in pyridoxine deficiency, and can be corrected by giving large amounts of pyridoxine (R6, T3). This has suggested that OCAs either may produce an absolute deficiency of pyridoxine or increase the body s requirement for this important coenzyme. There is evidence (Al, Bl) also that altered pyridoxine status may be associated with the mental depression that sometimes occurs in women taking OCAs. 

Pyridoxine status can be determined both by direct and indirect methods. Direct methods include determination of pyridoxal-5 -phosphate (PLP) in whole blood, and determination of urinary excretion of 4-pyridoxic acid (4-PA). The method of choice for quantification of both compounds is HPLC. Usually, whole blood concentrations of 35-110nmoll PLP... 

In two infants and a 6 year old child who received prolonged intravenous nutrition and MVI (USV Pharm.) at a dose of 1 ml per day, we found that the urinary excretion of unbound thiamine, pyridoxine and riboflavin was extremely high, suggesting that... 

JC Rabinowitz, EE Snell. Vitamin B group. XV. Urinary excretion of pyridoxal, pyridoxamine, pyridoxine, and 4-pyridoxic acid in human subjects. Proc Soc Exp Biol Med 70 235-240, 1949. 

Brown et al. (B25) confirmed the results of Coppini and Camurri (C9) on excretion of kynurenic and xanthurenic acids and, at the same time, examined the excretion of other tryptophan metabolites. Their data indicate that the high levels of all urinary metabolites excreted by pregnant subjects were lowered by pyridoxine administration. It must be remembered that the requirement for pyridoxine in pregnancy varies in the different animal species (C6). It was also found that the levels of pyridoxine in the fetal blood are elevated whereas those of maternal blood decrease (GIO). 

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). 

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. 

Interrelations among vitamin Be, hemoblastotic diseases, and tryptophan metabolite excretion have been investigated by Anderson (private communication to Professor L. Musajo) in a case of infantile leukemia showing spontaneous excretion of urinary kynurenine and 3-hydroxykynurenine, whose levels were normalized by daily administration of 50 mg pyridoxine. 

Morales and Lincoln (Mil) studied pyridoxine deficiency in 26 tuberculous children. Of these 20 received isoniazid therapy for various periods and clinical signs of Be deficiency were not observed. The ability to convert tryptophan to N -methylnicotinamide was used as a test for pyridoxine deficiency. Except for 1 case, all patients showed an increase in urinary N -methylnicotinamide excretion after tryptophan loading, and the authors admit the absence of pyridoxine deficiency. 

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. 

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. 

Gershoff and Prien (G6) found that normal subjects excrete significantly less xanthurenic acid and 4-pyridoxic acid and more citric acid than patients with chronic formation of calcium oxalate. A marked rise in excretion of calcium oxalate followed administration of tryptophan in these patients, whereas ingestion of pyridoxine was followed by a decrease in urinary oxalate. 

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... 

Deficiencies of methionine adenosyltransferase, cystathionine 8-synthase, and cystathionine )/-lyase have been described. The first leads to hypermethioninemia but no other clinical abnormality. The second leads to hypermethioninemia, hyperhomocysteinemia, and homo-cystinuria. The disorder is transmitted as an autosomal recessive trait. Its clinical manifestations may include skeletal abnormalities, mental retardation, ectopia lentis (lens dislocation), malar flush, and susceptibility to arterial and venous thromboembolism. Some patients show reduction in plasma methionine and homocysteine concentrations and in urinary homocysteine excretion after large doses of pyridoxine. Homocystinuria can also result from a deficiency of cobalamin (vitamin B12) or folate metabolism. The third, an autosomal recessive trait, leads to cystathioninuria and no other characteristic clinical abnormality. 

L9. Luhby, A. L., Brin, M., Gordon, M., Davis, P., Murphy, M., and Spiegel, H., Vitamin B metabolism in users of oral contraceptive agents. I. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. Amer. J. Clin. Nutr. 24, 684-693 (1971). 

Hydrolysis of pyridoxal phosphate to pyridoxal followed by oxidation to 4-pyridoxic acid is the major catabolic pathway for vitamin B6 in most mammalian species. In cats, however, the major urinary metabolites are pyridoxine 3-sulfate and N-methylpyridoxine (Cobum and Mahuren, 1987). Also, in humans receiving very large vitamin B6 intakes excretion of 5-pyridoxic acid may become significant (Mahuren et aL, 1991). 

Ubbink, J. B., Serfontein, W. J., Becker, P. J., and dc Villiers, L. S. (1987). Effect of different levels of oral pyridoxine supplementation on plasma pyridoxal-S -phosphate and pyridoxal levels and urinary vitamin B-6 excretion. Am. J. Clin. Nutr. 46,78-85. 

Ubbink (1992) reviewed the chromatographic methods used to study vitamin Be- He noted that with the advent of HPLC, TLC is rarely used as a quantitative technique in the analysis of this vitamin however, it is still a convenient qualitative method to study the metabolism of vitamin B. Cobum and Mahuren (1987) examined vitamin B6 metabolism in cats and found that although 70% of the ingested carbon-labeled pyridoxine appeared in the urine, only 2-3% of the excreted dose was 4-pyridoxic acid. Using TLC, it was determined that pyridoxine 3-sulfate and pyridoxal 3-sulfate were the major urinary metabolites of the ingested pyridoxine. 

Analysis of urine samples for the other Be vitamers is difficult due to high concentrations of other interfering compounds present in urine. Ubbink et al. (150) demonstrated that an anion exchange column cleanup procedure was effective in removing interfering urinary compounds. The purified urine extract was then analyzed by cation exchange HPLC and fluorescence detection. Urinary Bg vitamer excretion in a fasting person was below the sensitivity limit of the HPLC procedure used. However, the method was suitable to study urinary Bg vitamer excretion in pharmacokinetic studies of pyridoxine supplementation (150). 

Slightly elevated urinary oxalate excretion and plasma oxalate levels in patients may indicate another not yet well-defined form of primary hyperoxaluria (type III ) (Monico and Milliner 1999 Rose 1988). Patients have severe recurrent urolithiasis, but may respond even to low doses of pyridoxine (Edwards and Rose 1991 Hoppe et al. 2007). 

The success of D-penicillamine as an antirheumatic drug have prompted the search for other thiols with improved risk/benefit relationship. Recently 5-thio-pyridoxine f5 was shown to have therapeutical value in rheumatoid arthritis. This thiol caused no increased urinary copper excretion, had no antipyridoxin effect, had no effect on skin collagen and did not enter into SH/SS exchange with the amino acid cystine. Thus, the redox potential and reactivity of thiopyridoxine appears to be somewhat different from that of D-penicillamine. 

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