Amino Acid Requirements

Recommendations for the intake of individual amino acids are largely based upon the pioneering work of W. C. Rose and his colleagues in the 1950s ( 152, 153). Irwin and Hegsted have reviewed these and other studies of amino acid requirement levels published before 1971 ( 160). Rose's studies are all N balance studies in which young male subjects were placed upon diets whose N intake consisted of a mixture of crystalline amino acids. The intake of a single amino acid could be altered, and the N balance measured. Because of the expense of the amino acid diets and the great difficulty in performing serial N balance studies at different intakes, Rose and colleagues were only able to study a very limited number of subjects per amino acid. Problems with interpreting the N balance data for a limited number of subjects cloud the extrapolation of these data to populations (161, 162 and 163); yet these N-balance data remain the basis for the present amino acid recommendations in adults (Table^M). Rose's data have been confirmed in the more recent study of Inoue et al., also using the N balance technique ( 164), but the data set for requirements for individual amino acids is extremely slim.

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Table 2.14 Estimates of Dietary Amino Acid Requirements (mg/kg/day) by Age Group

An alternative approach has been taken by Young and colleagues (162, 165, 166), based upon the method of Harper and others to assess amino acid requirements in growing animals by using amino acid oxidation as an index of dietary sufficiency. Animals fed an insufficient amount of a specific individual amino acid reduce their oxidation of the deficient amino acid to obligatory levels. Oxidation of the dietary-deficient amino acid will remain at obligatory oxidation levels until the requirement level is met. Then, as dietary amino acid intake rises above requirement, the excess amino acid is oxidized. Therefore, a two-line curve should appear when amino acid oxidation is plotted against amino acid intake: a flat line below requirement (indicating obligatory oxidation) and a rising curve above the requirement (indicating oxidation of excess amino acid intake). The requirement level for the amino acid should be the intersection of the two curves, i.e., where oxidation of excess amino acid begins (167).

The amino acid oxidation curve has been assessed in growing animals placed on diets in which the intake of one amino acid is manipulated. A 14C-labeled amino acid tracer of the manipulated amino acid is added to a test meal to measure oxidation as a function of dietary amino acid intake ( 168). This approach has been applied by Young and coworkers to assessing human amino acid requirements using nonradioactive, stable, isotopically labeled amino acid tracers. From the results of these studies, Young proposed that the present recommended essential amino acid requirements for isoleucine, leucine, lysine, phenylalanine/tyrosine, and valine be increased in healthy adults (165, 166). These estimates, which are 2 to 3 times the RDAs for adults (Iab]e...2J...4.), have been challenged on methodologic and theoretical grounds by Millward et al. (169). Both Young (165, 166, 170) and Millward (171) have provided experimental data from stable isotope tracer studies in humans to support their arguments for and against increasing the recommended intakes of essential amino acids.

Zello et al. (172) have taken a different approach to the measurement of amino acid requirements using the oxidation of an amino acid tracer as an index. Rather than administer and measure the oxidation of an amino acid tracer of the amino acid that is being reduced in the diet, they use another essential amino acid tracer as the indicator of N balance. Nitrogen balance becomes negative when a single amino acid is deficient in the diet because the excess amino acids that cannot be incorporated into protein when one amino acid is deficient are oxidized, which increases urea production. As discussed above, measurement of the increase in urea production is fraught with problems, which is why direct oxidation of the indicator amino acid is measured using an amino acid tracer. When dietary intake of the test amino acid is below requirement levels, oxidation of the indicator amino acid increases as excess amino acids are wasted. The key to this method is the availability of an indicator amino acid tracer whose oxidation can be accurately and precisely measured, which differs from the test amino acid being manipulated in the diet. Using this approach and [1-13C]phenylalanine as the indicator amino acid, Zello et al. determined a requirement level for dietary lysine of 37 mg/kg/day ( 173), which supports Young's higher estimate of lysine requirements (T§ble 2.:14.).

Histidine, which is essential to the diet of the rat, has been hard to define as essential to the diet of adult humans ( 160). In the 1973 FAO/WHO report, no requirement for histidine was given for adults (158), but the 1985 WHO/FAO/UNU report (156) listed a requirement for histidine of 8-12 mg/kg/day (Ia.ble...,2...,14). This requirement in adults is based upon extrapolation of data from infants (157). The limited studies of adults indicate that the requirement for histidine may be less than 2 mg/kg/day (174). However, this requirement has not been clearly documented in normal subjects (154). Proving that histidine is essential in adults has largely been restricted to studies of renal failure (8). Why is it so difficult to determine whether histidine is essential in adults, using conventional dietary techniques, when there is little evidence that a metabolic pathway for histidine synthesis exists in humans (17)? The difficulties occur because the requirement for histidine is small and the stores of histidine in the body are large (8, 154). Histidine is particularly abundant in hemoglobin and carnosine (the dipeptide b-alanylhistidine, which is present in large quantities in muscle). Furthermore, gut flora synthesize an unknown amount of histidine, which may be absorbed and used. Histidine must be removed from the diet for more than a month to observe effects, and those effects are indirect measures of histidine insufficiency (a fall in hemoglobin and rise in serum iron) rather than alterations in conventional indices (N balance). Thus, even though little direct evidence for histidine synthesis in humans exists, our estimates for the necessity of dietary histidine intake in adults are still largely inferential.

In contrast to histidine, arginine is synthesized in large amounts in the body for the production of urea. However, like that of cysteine and tyrosine, synthesis of arginine depends upon the availability of precursors, ornithine and citrulline. Although adequate amounts of arginine, ornithine, and citrulline are normally present in the liver to operate the urea cycle, the synthesis of ornithine, from which arginine and citrulline are produced, may be limited ( 17). Because arginine is synthesized in the body from ornithine, it is not an essential amino acid, but it is indispensable for optimal growth in several species of young mammals (154).

Rose et al. observed an adequate N balance in adult subjects fed an arginine-free diet, and Snyderman et al. found no health problems or lack of weight gain in infants fed an arginine-free diet (8). Carey et al. (175) placed adult subjects on a diet devoid of arginine for 5 days. They measured indices of urea cycle activity: plasma ammonia concentration, daily urinary excretion of orotic acid, and urinary N excretion. They found no alterations due to the arginine-free diet. These results would lead to the conclusion that arginine is nonessential to the diet of humans; yet, there is little evidence that the body synthesizes ornithine from glutamate in substantial amounts (Fig 2.4).

Castillo et al. simultaneously measured arginine, ornithine, and citrulline kinetics in healthy adults, using stable isotopically labeled tracers ( 87). Their studies show that the fluxes of all three amino acids are very low in blood and do not reflect the active urea cycle component, which appears to be highly compartmentalized in the liver. Ornithine and citrulline fluxes were comparable, but were only one-third the rate of arginine turnover, and a relatively small fraction of the ornithine tracer appeared in plasma arginine or citrulline. The low flux of ornithine suggests that very little synthesis occurs, but direct measurements of ornithine synthesis are lacking. Inferential measurements do suggest ornithine synthesis. For example, 15N tracer is transferred from glycine into glutamate and into the metabolic products of glutamate, including ornithine and proline (23).

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