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VALINE DEFICIENCY IN RATS
1205
r
'
Fig. 1 Neurons of the red nuclei from rats fed the following diets for 25 days: (A)
valine-free; (B) control, ad libitum; (C) control, pair-fed to valine deficients; (D) iso-
leucine-, leucine-, and valine-free. Cell swelling, chromatolysis and nuclear displacement are
apparent in neurons from valine-deprived rats but not in the neurons of controls or of rats
deprived of all three branched chain amino acids. Photographed at a magnification of 450X.
Stain: hematoxylin-eosin.
at the cellular level as a disaggregation of
polysomes. The cellular response of liver
was characteristic of tryptophan deficiency
and not of a deficiency of other essential
amino acids, apparently because trypto
phan is the rate-limiting amino acid for
protein synthesis in this organ (12). That
branched-chain amino acids limit the rate
of protein synthesis in muscle has been
demonstrated ( 13). Our data are consistent
with the possibility that valine may limit
the rate of protein synthesis in the red
nuclei!and perhaps, judging from Scott's
work, in other parts of brain.
We observed that neurological signs did
not occur and the red nuclei appeared
normal when rats were fed diets lacking
all three branched-chain amino acids.
These data strongly suggest that the nerve
tissue damage characteristic of valine de
ficiency actually is a consequence of amino
acid imbalance. In other words, it ap
parently was not simply a lack of valine
which caused the nerve damage but the
presence in the valine-free diet of isoleu-
cine and leucine.
Branched-chain amino acids compete
with one another and with other neutral
amino acids for transport into brain (14).
The essential amino acid supply for pro
tein synthesis comes both from diet and
from tissue breakdown (15). In protein
deficiency, amino acids from muscle (and
presumably from other extracerebral tis
sues) are salvaged to maintain brain pro
tein ( 16). In an animal fed a diet lacking
all three branched-chain amino acids, one
might anticipate that a small but balanced
supply of isoleucine, leucine and valine
from breakdown of extracerebral tissues
would compete for entry into brain. In the
rat fed a diet deficient in valine alone, the
relatively high concentrations of leucine
and isoleucine in the diet might inhibit the
transport into brain of valine from tissue
breakdown. Thus, because of its unique
transport system which limits entry of
amino acids, brain might suffer more from
valine deficiency than other organs. Suit
able experiments to test this hypothesis
are in progress.
LITERATURE CITED
1. Rose, W. C. & Eppstein, S. H. (1939) The
dietary indispensability of valine. J. Biol.
Chem. 127, 677-684.
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120G CUSICK, KOEHLER, FERRIER AND HASKELL
2. Womack, M. & Rose, W. C. (1936) The
relation of leucine, isoleucine and norleucine
to growth. J. Biol. Chem. 116, 381-391.
3. Snyderman, S. E., Boyer, A., Norton, P. M.,
Roitman, E. & Holt, L. E., Jr. (1964) The
essential amino acid requirements of infants.
IX Isoleucine. Am. J. Clin. Nutr. 15, 313-
321
4. Snyderman, S. E., Holt, L. E., Jr., Smellie,
F., Boyer, A. & Westall, R. G. (1959) The
essential amino acid requirements of infants.
Valine. Am. J. Dis. Child. 97, 186-191.
5. Scott, E. B. (1964) Histopathology of
amino acid deficiencies. VII. Valine. Experi
mental and Molecular Pathology 3, 610-621.
6. Wannemacher, R. W., Jr. & Allison, J. B.
( 1968 ) Plasma amino acid concentrations in
relation to protein synthesis. In: Protein Nu
trition and Free Amino Acid Patterns
(Leathern, J. H., ed.), Rutgers University
Press, New Brunswick, N.J., pp. 206-227.
7. Ranhotra, G. S. & Johnson, B. C. (1965)
Effect of feeding different amino acid diets on
growth rate and nitrogen retention of wean
ling rats. Proc. Soc. Exp. Biol. Med. 118,
1197-1201.
8. Draper, H. H., Bergan, J. G., Chi!, M.,
Csallany, A. S. & Boaro, A. V. (1964) A
further study of the specificity of the vitamin
E requirement for reproduction. J. Nutr. 84,
395-400.
9. Greenfield, H. & Briggs, G. M. (1971) Nu
tritional methodology in metabolic research
with rats. Ann. Rev. Biochem. 40, 549-572.
10. Parsons, P. L., Shrader, R. E. & Zeman, F. J.
(1976) Adrenal function in young of pro
tein-deprived pregnant rats. J. Nutr. 106,
392-404.
11. Ferrare, A., Roizin, L. & Givner, I. (1947)
Ocular changes in rats on diets deficient in
amino acids. II. Corneal dystrophy due to
valine deficiency. Arch. Ophth. 38, 342-352.
12. Munro, H. N. (1968) Role of amino acid
supply in regulating ribosome function. Fed.
Proc. 27, 1231-1237.
13. Fulks, R. M., Li, J. B. & Goldberg, A. L.
( 1975 ) Effect of insulin, glucose, and amino
acids on protein turnover in rat diaphragm.
J. Biol. Chem. 250, 290-298.
14. Oldendorf, W. H. & Szabo, J. (1976)
Amino acid assignment to one of three blood-
brain barrier amino acid carriers. Am. J.
Physiol. 230, 94-98.
15. Wannemacher, R. W., Jr. (1967) Protein
synthesis in various tissues from animals at
different stages of protein-calorie malnutrition.
Seventh Int. Cong. Nutr. 5, 205-210.
16. Dallman, P. R. & Spirito, R. A. (1972)
Brain response to protein undemutrition:
Mechanism of preferential protein retention.
J. Clin. Invest. 51, 2175-2180.
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Errata
Cusick, P. K., Koehler, K. M., Ferner, B. & Haskeil, B. E. (1978) The
neurotoxicity of valine deficiency in rats. J. Nutr. JOS, 1200-1206. The vita
min mixture supplied (per 100 g diet) 75 mg choline chloride (not 7.5) and
7.5 mg ascorbic acid (not 1.75).
Tagari, H. & Bergman, E. N. (1978) Intestinal disappearance and portal
blood appearance of amino acids in sheep. J. Nutr. 108, 790-803. The fol
lowing section of text was deleted from tibe manuscript.
Some of the missing amino acids may
have been utilized by intestinal bacteria to
produce diaminopimdic acid or other N
compounds (11, 29, 30) and may have
never left the intestinal lumen.
Quantitative correlations of gut disap
pearance and portal appearance of amino
acids. While the above metabolic pathways
may account for significant amounts of
missing amino acids, the great SE one finds
in this type of work (5, 7) must be taken
into consideration. One of the main aims of
this study was to find a possible correla
tion between gut disappearance of amino
acids and some easily sampled and deter
mined blood criterion. Indeed, when gut
disappearance was correlated with portal
appearance, it was found that when smaller
amounts of amino acids disappear from the
gut, the amounts of the same amino acid
appearing in the portal blood usually were
even smaller. The same was true when the
amounts of amino acids passing through
the pylorus were correlated with portal
appearance.
Also of importance is that the arterial
concentrations of several essential amino
acids were significantly correlated with the
quantities of amino acids passing through
the pylorus and also to the quantities dis
appearing from the intestine (table 9).
One major exception, however, was lysine
and, in this case, part of the missing lysine
might have been metabolized to NML
where concentrations in arterial circulating
blood were greater in sheep fed the H.P.
TABLE 9
Significance of correlations between amounts of amino
acids (g) passing through the pylorus (Py) or dis
appearing between pylorus and ileum (Py-I)
with amounts of amino acids circulating in ar
terial blood (A) in sheep fed high protein
(H.P.) or medium protein (Af.P.) diets1
Correlation coeffi
cients between2Amino
acidThreonineJ
Cystine
ValineIsoleucineLeucinePhenylalanineLysineHistidineMethionineNon-essential
amino acidsPy
and Ar
= 0.76N.
S.3
r = 0.88"r
= 0.79"r
= 0.96r
= 0.72"N.S.N.S.N.S.N.S.Py-Iand
Ar
= 0.84N.S.
r = 0.79N.
S.r
= 0.88"N.S.N.S.N.S.N.S.N.S.
'H.P. diet: 5 replicates; M.P. diet: 4 replicates,
for each amino acid. 2Determined on 9 pairs of
results for each amino acid. ' N.S. : Not signifi
cant; P < 0.05, *P < 0.01.
diet. This may explain the lack of correla
tion between the amounts of intestinal dis
appearance and arterial circulating lysine.
The glutathione pathway for cystine was
previously discussed and this may be one
of the reasons why arterial cystine concen
tration differences were not found. It must
be considered that dietary differences for
arterial plasma amino acid concentrations
will tend to be masked by the regulatory
effect of the liver. In spite of this, however,
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