Vitamin relative dose-response

During the development of vitamin A deficiency in experimental animals, the plasma concentration of RBP falls, while the liver content rises. The administration of retinol to deficient animals results in a considerable release of holo-RBP from the liver. This is a rapid effect on the release of preformed apo-RBP in response to the availability of retinol, rather than an increase in the synthesis of the protein. There is no evidence that retinol controls the synthesis of RB P (Soprano et al., 1982). This provides the basis of the relative dose response (RDR) test for liver stores of vitamin A (Section 2.4.1.3) administration of a test dose of retinol gives a considerably greater increase in plasma retinol, bound to RBP, in deficient subjects than in those with adequate liver reserves, because of the accumulation of apo-RBP in the liver. 

The Relative Dose Response (RDR) Test The RDR test is a test of the ahUity of a dose of vitamin A to raise the plasma concentration of retinol several hours later, after chylomicrons have heen cleared from the circulation. What is being tested is the ahUity of the liver to release retinol into the circulation. In subjects who are retinol deficient, a test dose will produce a large increase in plasma retinol, because of the accumulation of apo-RBP in the liver in deficiency (Section 2.2.3). In those whose problem is due to lack of RBP, then little of the dose will be released into the circulation. An RDR greater than 20% indicates depletion of liver reserves of retinol to less than 70 /rmol per kg (Underwood, 1990). 

Tanumihardjo SA, Koellner PG, Olson JA. The modified relative-dose-response assay as an indicator of vitamin A status in a population of well-nourished American children. Am J Clin Nutr 1990 52 1064-7. 

Tanumihardjo SA, Muhilal, Yuniar Y, Permaesih D, Sulaiman Z, Karyadi D, Olson JA. Vitamin A status in preschool-age Indonesian children as assessed by the modified relative-dose-response assay. Am J Clin Nutr 1990 52 1068-72. 

Van Jaarsveld, P. J., Faber, M., Tanumihardjo, S. A., Nestel, P., Lombard, C. J., and Spinnler Benade, A. J. (2005). 3-carotene-rich orange-fleshed sweet potato improves the vitamin A status of primary school children assessed with the modified-relative-dose response test. Am. ]. Clin. Nutr. 81, 1080-1087. 

The plasma concentration of vitamin A falls only when the liver reserves are nearly depleted. In deficiency there is accumulation of apo-RBP in the liver, which can only be secreted when vitamin A is available. This provides the basis for the relative dose-response test for vitamin A status — the ability of a dose of retinol to raise the plasma concentration several hours later, after chylomicrons have been cleared from the circulation. 

SA Tanumihardjo, HC Furr, JW Erdman Jr, JA Olson. Use of the modified relative dose response (MRDR) assay in rats and its application to humans for the measurement of vitamin A status. Eur J Clin Nutr 44 219-224, 1990. 

Duitsman PK, Cook LR, Tanumihardjo SA, Olson JA (1995) Vitamin A inadequacy in socioeconomically disadvantaged pregnant Iowan women as assessed by the modified relative dose response (MRDR) test. Nutr Res 15 1263-1276... 

This method can be used to compensate for inhibition of a biochemical pathway which results in a deficiency of an essential metabolic product. Detailed variations of the method are provided by Dayan et al.7 and Amagasa et al.1 The inhibitor concentration should be no higher than that required for strong herbicidal effect. Metabolite concentrations should be below that which is phytotoxic. For example, certain amino acids such at methionine, are growth inhibitors at relatively low concentrations. So, in preliminary work, dose-response studies should be done with amino acids to find the maximum concentrations that do not inhibit growth. Then, seeds of test plants should be imbibed in solutions of the phytotoxin with and without metabolite solutions. Amino acids, tricarboxylic acid cycle intermediates, vitamins, nucleotides, and reducing agents have all been used in complementation studies to elucidate modes of action of a variety of phytotoxins. Examples of each of these is provided by Dayan et al.7... 

The potencies of various tocopherols, K vitamins, ubiquinones, and similar substances in the prevention of respiratory decline have been assayed by supplementation of graded dose levels to the whole homogenate system. For each dose level, averages of at least four experiments were established. From the dose-response curves, the 50 % effective dose (EDbo) was derived. The EDso for df-a-tocopherol was found to be 1.1 ng per 3 ml of medium containing 50 mg of homogenized liver (Table VII). A comparison of the potencies of a-, /3-, 7-, and 5-tocopherols gave the same relative order of activity as the resorption sterility assay for vitamin E. df-a-To-copheryl acetate demonstrated only 3 % of the activity of the free vitamin. a-Tocopherylquinone was about 10% as active as tocopherol itself. The Simon metabolite (Simon et al., 1956) (Fig. 4) showed 40% of the activity of di-a-tocopherol, in spite of the fact that it was supplied in the quinone form. 

When utilization tests were run on a group of 18 male and 7 female human subjects, wide variations in blood level responses were found, particularly among the males.36 [Both in animals (rats) and humans the two sexes respond somewhat differently.] When 134,000 ig. of vitamin A in four different forms, viz., vitamin A alcohol, vitamin A acetate, vitamin A natural ester No. 1, and vitamin A natural ester No. 2, was fed to the group of 18 males on four different occasions, the serum levels found after 6 hours ranged from 178 to 1423 ig. per 100 ml., 122 to 1170 ig. per 100 ml., 110 to 1183 ig. per 100 ml., and 114 to 1230 ig. per 100 ml., respectively. These nearly 10-fold variations in serum levels do not, of course, indicate 10-fold variation in need, but they do show that the vitamin when given in relatively large doses does behave very differently in different individuals. 

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