Loading tests, metabolic tryptophan

Metabolic loading tests and the determination of enzyme saturation with cofactor measure the ability of an individual to meet his or her idiosyncratic requirements from a given intake, and, therefore, give a nearly absolute indication of nutritional status, without the need to refer to population reference ranges. A number of factors other than vitamin intake or adequacy can affect responses to metabolic loading tests. This is a particular problem with the tryptophan load test for vitamin Be nutritional status (Section 9.5.4) a number of drugs can have metabolic effects that resemble those seen in vitamin deficiency or depletion, whether or not they cause functional deficiency. 

The tryptophan load test for vitamin Bg nutritional status (the ability to metabolize a test dose of tryptophan) is one of the oldest metabolic tests for functional vitamin nutritional status. It was developed as a result of observation of the excretion of an abnormal-colored compound, later identified as the tryptophan metabolite xanthurenic acid. 

Xanthurenic and kynurenic acids, and kynurenine and hydroxykynurenine, are easy to measure in urine, so the tryptophan load test, the ability to metabolize a test dose of 2 to 5 g (150 to 380 /xmol per kg of body weight) of tryptophan, was widely adopted as a convenient and sensitive index of vitamin Bg nutritional status. 

Early studies of vitamin Be requirements used the development of abnormalities of tryptophan or methionine metabolism during depletion, and normalization during repletion with graded intakes of the vitamin. Although tryptophan and methionine load tests are unreliable as indices of vitamin Be status in epidemiological studies (Section 9.5.4 and Section 9.5.5), under the controlled conditions of depletion/repletion studies they do give a useful indication of the state of vitamin Be nutrition. More recent studies have used more sensitive indices of status, including the plasma concentration of pyridoxal phosphate, urinary excretion of 4-pyridoxic acid, and erythrocyte transaminase activation coefficient. 

Brown et al. (B24) also observed in a few patients, without bladder tumor, that the surgical excision of most of the neoplastic tissue was followed by a return to normal tryptophan metabolism, after the loading test. In cases of bladder cancer, on the other hand, some of the most severe disturbances were observed in patients who had been clinically free of cancer for 1-13 years. 

A preliminary investigation on tryptophan metabolism in aged subjects (over 70 years old) was carried out by Avogaro, Crepaldi, and Parpajola and by Benassi and Allegri, using the tryptophan loading test. 

Thus, an anomaly after tryptophan loading exists in these patients in comparison to normal controls. Other results have been reached by Price et al. (P12) who, by means of their 2 g loading test, found that 6 patients with schizophrenia had a distinctly abnormal tryptophan metabolism while 13 other patients metabolized tryptophan in a normal manner. The patients with abnormal metabolism excreted significantly... 

Raskin (R4) tried the DL-tryptophan (10 g) loading test on 12 patients with infectious hepatitis, 72 with chronic hepatitis following the infectious phase, and 5 with Parkinsons disease. It was shown, by the xanthurenic acid test, that the chronic form was accompanied by a disturbance of tryptophan metabolism, and that xanthurenuria persisted even when amounts of pyridoxine were excreted, i.e., in a state of hyper-vitaminosis. Vitamin Bs was therefore well above the minimal daily requirement of the patients, thus showing that other factors are involved in the abnormal excretion of xanthurenic acid. 

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). 

Wl. Wachstein, M., and Gudaitis, A., Disturbance of vitamin Bi metabolism in pregnancy. II. The influence of various amounts of pyridoxine hydrochloride upon die abnormal tryptophan load test in pregnant women. J. Lab. CUn. Med. 42, 98-107 (1953). 

Xanthurenic and kynurenic acids, and kynurenine and hydroxykynurenine, are easy to measure in urine, so the tryptophan load test (the ability to metabolize a test dose of 2—5 g of tryptophan) has been widely adopted as a convenient and very sensitive index of vitamin nutritional status. However, because glucocorticoid hormones increase tryptophan dioxygenase activity, abnormal results of the tryptophan load test must be regarded with caution, and cannot necessarily be interpreted as indicating vitamin B deficiency. Increased entry of tryptophan into the pathway will overwhelm the capacity of kynureninase, leading to increased formation of xanthurenic and kynurenic acids. Similarly, oestrogen metabolites inhibit kynureninase, leading to results that have been misinterpreted as vitamin B deficiency. 

The metabolism of methionine, shown in Figure 11.22, includes two pyridoxal phosphate-dependent steps cystathionine synthetase and cystathionase. Cystathionase activity falls markedly in vitamin deficiency, and as a result there is an increase in the urinary excretion of homocysteine and cystathionine, both after a loading dose of methionine and under basal conditions. However, as discussed below, homocysteine metabolism is affected more by folate status than by vitamin status, and, like the tryptophan load test, the methionine load test is probably not reliable as an index of... 

Abnormal response to a metabolic load, such as the inability to metabolize a test dose of histidine in folate deficiency (Section 10.10.4), or tryptophan in vitamin Be deficiency (Section 9.5.4), although at normal levels of intake there may be no metabolic impairment. 

Hodgkin s Disease and Other Hematological Disorders. A study of the relationship between tryptophan metabolism and Hodgkin s disease was carried out in this laboratory by means of tryptophan loadings which were followed, a week later, by a second test in the same patients with tryptophan and pyridoxine (C12). 

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