Failure of oral L-histidine to influence appetite or affect zinc metabolism in man: a double-blind study1 Paul
J. Schechter,2
M.D.,
Ph.D.
and Nellikunja
J. Prakash,
Ph.D.
ABSTRACT
L-Histidine, 4 g/day in gelatin capsules, was administered orally to eight normal volunteers for 2 weeks in a double-blind, balanced, crossover study with 2 weeks of placebo treatment. Body weight, serum and urinary zinc and histidine concentrations, as well as subjective ratings of appetite, taste and smell perception, and food intake were monitored. L-Histidine therapy had no significant effect on appetite, taste and smell perception, food intake, or body weight. Similarly, no effects were observed on total serum zinc, albumin-bound zinc or a,-macroglobulinbound zinc concentrations, or on urinary histidine excretion. Serum histidine concentrations increased with therapy. Urinary zinc excretion was increased significantly after 1 week, but not after 2 weeks of L-hlstidlne therapy. It can be concluded that oral L-histidlne, at the dose used, has no value as an anorectic agent. Am. I. Clin. Nut,. 32: 1011-1014, 1979.
Oral administration of large doses of Lhistidine to man has been reported to produce alterations in zinc metabolism accompanied by anorexia, taste and smell dysfunction, mental changes, cerebellar dysfunction, and loss of body weight (1-3). These signs and symptoms have been attributed to acute body loss of zinc since they correlated with a decrease in serum zinc concentrations and elevations in urinary zinc excretion and were rapidly reversed following oral administration of zinc ion, despite continued L-histidine administration (2, 3). The mechanism proposed for this syndrome involves a stripping of zinc from normal binding sites on serum albumin by histidine and excretion of small molecular weight histidine-zinc ligands in the urine (2). The loss of appetite induced by oral Lhistidine administration has been used in open studies in nonobese and obese subjects (1,3,4) to produce controlled weight loss and has been proposed as a new approach to clinical appetite control. The present doubleblind study was undertaken to attempt to verify the previous uncontrolled studies and to investigate the possible efficacy of oral Lhistidine as anorectic therapy in man. TheAmerican
Journal
of Clinical
Nutrition
32: MAY
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
1979,
Methods Eight male volunteers (ages 32 to 38) were used as subjects. The subjects were free of any chronic diseases, not under therapy with any medication, followed a normal dietary regime and had not gained or lost more than 5 kg within the 6 months before the start of the study. The mean body weight of the subjects before treatment was 71.6 kg (range: 59.8 to 80.5). All subjects were studied during the same 4-week period during the months of September and October. L-Histidine was prepared in capsules. Each capsule was formulated to contain L-histidine base, 250 mg, with lactose (80 mg) and hydrogenated castor oil (15 mg) as excipients. Placebo capsules with an identical appearance were prepared using 330 mg lactose and hydrogenated castor oil (15 mg). L-hiStidifle and placebo capsules were administered in a double-blind balanced, cross-over design. Each subject was randomly assigned to one of two groups. Group I (four subjects) received 14 days of placebo followed by 14 days of L-histidine (4,g/day); group II (four subjects) received 14 days of L-histidine followed by 14 days of placebo. Four capsules were taken 4 times per day with 200 ml water, before breakfast, at 10 AM, 3 PM, and at bedtime. This number of capsules (16 size 1 capsules per day) was considered maximal for subject compliance with the protocol and for practicalness. No attempt was made to modify the subjects
normal
purpose
and design
of the study.
the Centre
de Recherche
‘From
diet
although
all
were
Merrell
aware
International,
16, rue d’Ankara, 67084 Strasbourg Cedex, France. 2Author to whom requests for reprints should addressed. pp.
1011-1014.
Printed
in U.S.A.
the
of
be
1011
1012
SCHECHTER
Subjects scales each place along length): No
AND
were instructed to complete visual analog evening by placing an X at the appropriate four lines (each of which measured 10 cm in
Body
to eat
today
weight
The day
desire
PRAKASH
changes
course
Ravishingly
i
Food tasted like paper today
in body
for each hungry
today
A)
(line
B)
(line C)
I
Smells and taste today had more pleasant qualities than usual
Ate less today
I-
I
Ate more
Line A was designed to evaluate appetite; line B, to detect the presence of hypogeusia and/or hyposmia; line C, dysgeusia and/or dysosmia and line D to estimate food intake. Responses were recorded as the distance of the X (to the nearest one tenth centimeter) from the lefthand limit of the line. Biochemical
determinations
Blood and 24 hr urinary samples were collected from each subject immediately before starting the study and at weekly intervals thereafter. Blood was sampled approximately 1 hr after a dose in the fasted state (except for the ingestion of the four capsules plus water). Serum was obtained with precautions to avoid zinc contamination as previously described (5). Urine was collected in plastic containers without preservative. Histidine concentrations were estimated in serum and aliquots of 24-hr urine samples using the method of Nakamura and Pisano (6). Urinary and total serum zinc, as well as albuminbound zinc and az-macroglobulin-bound zinc in serum, were estimated using the procedures previously described (7).
Results Subjective
evaluation
A comparison of the responses of each subject on the same respective day of each course did not reveal any difference (P>> 0.05, paired t test) on any day for either lines A, B, C, or D between placebo and L-hiStldlfle treated groups. In seven of eight subjects no difference between placebo and L-hlstldlne was found when average values for each line over the entire 14-day courses were considered (t test, 2-tailed). In one subject (subject II) the mean values recorded for line A (3.8 cm) and line D (3.8 cm) during placebo therapy (course 2) were significantly lower (P < 0.005) than those during the L-hlStichne course (4.9 and 4.9, respectively). No differences in lines B or C were noted in this subject.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
each 14in Table
(line
P
usual
over
are given
I could taste and smell food especially well today
Some smells and tastes today had bizarre, unpleasant quality than
weight
subject
today
than
usual
1. No difference and L-histidine test). Serzrn,z
and
(line
D)
was found between therapy (P >> 0.05,
urinary
placebo paired I
histidine
Compared to pretreatment values, the mean change in serum histidine concentration after 1 week of L-histidine therapy was significantly greater (P < 0.001, paired I test) than the change after 1 week of placebo (+ 49.2 tmoles/ml versus 4.7). A similar, al-
though
smaller
change,
was
present
(Table
when values after 2 weeks of each course considered (+ 33.7 smo1es/ml versus
-
1)
was 85,
P < 0.05).
Urinary free histidine excretion, however, failed to differentiate between subjects taking L-histidine and those taking placebo. Compared to pretreatment values, the increase in urinary histidine after either 1 or 2 weeks of therapy was not significantly different between placebo and L-histidine treated subjects (P>> 0.05, paired I test). Serum
and
urinary
zinc
Before the onset of any therapy, the mean total serum zinc of the subjects was 88.5 sg/ 100 ml (Table 1); a value in agreement with those we have previously reported for normal subjects (5, 7). The differences between pretreatment total serum zinc concentrations and those after 2 weeks of L-hiStidine therapy were not different from values after 2 weeks of placebo (P>> 0.05, paired t test). Pretreatment mean concentrations of albumin-bound zinc and armacroglobulinbound zinc were 60.3 g/l00 ml (68.9% of total zinc) and 27.3 tg/100 ml, respectively. No significant differences were found between changes after L-histidine treatment and
ZINC
TABLE
METABOLISM
IN MAN
1013
1
Body weight change, serum histidine and zinc concentrations, and urinary histidine treatment with placebo (P) for 2 weeks and L-histidine (H), 4 g/day for 2 weeks Subject
Age
Body wt
Treatment order
n,t,al
Serum A
P
H
Initial
kg
1 II III IV V VI VII VIII
38 38 34 37 35 32 35 33
P-H H-P H-P P-H H-P P-H H-P P-H
Means
histidine P
80.5 74.3 75.7 70.9 62.7 59.8 79.6 69.5
+0.1 -0.4 +0.1 +1.6 +0 .4 +0.1 +0.4 0
+0.3 +0.8 0 -2.1 +0 .6 +0.2 +1.1 +0.6
71.6
+0.3
+0.2
a2-macroglobulin-bound
H
90.5
95.3 107.5 100.0
84.8 94.0 100.0 73.5
93.5 95.0 102.5 90.0 96.8
zinc
1465 710 1459 1540
97.0
98.5
1786
84.5 84.8 87.5 88.3
227.5 147.8 87.3 130.5
922 2135 1459 1435
concentra-
Discussion
Decreased food intake and weight loss are invariable features of zinc deficiency in rats (8, 9). The effects of L-histidine, however, on appetite and body weight of rats are unclear. The addition of excess L-histidine to the diet of rats has been reported to depress growth rate (10). In another study, however, chronic oral administration oflarge doses of histidine to rats had no effect on weight gain despite a increase
in urinary
zinc
excretion
(11). The administration of L-histidine in large doses to man in uncontrolled studies has been reported to produce an experimental, reversible zinc deficiency accompanied by taste and smell abnormalities, loss of appetite, and decreased food intake (2-4). A dose of 4.2 g of L-hlstidlne was said to produce anorexia within 4 days at which time there was no
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
Total H
Initial
hr
1460 846 944 1781
pg
1509 2000 1365 1008
Urinary
H
P pg /24
104 104 100 64 88 100 116 108 92 104 104 96 99 98
92 84 84 88
Zn
Initial
ml
108 92 96 96
76
962 2150 1714 1712
Zn
P lilY)
96 92 84 92
492 2987 1414 1267 1644 1231
Serum
after
637 284 479 246 353 418 456 333 401
H hr
850 980 478 560 480 480 366 352 281 577 760 644 577 598 511 502 538 587
alteration in urinary zinc excretion or serum zinc concentrations (3). With greater doses of L-histidlne, urinary zinc excretion is increased and serum zinc concentrations decreased (2, 12).
In the present of oral
double-blind
L-histidine,
petite,
subjective
study
4 g/day,
no effect
is found
on
ap-
taste and smell perception, in normal volunteers. Serum
or body weight histidine concentrations are elevated after oral L-histidine administration. No significant change in urinary free histidine excretion can be found after histidine treatment corn-
pared to placebo treatment, consistent with the efficient resorptive mechanism for amino acids
3- to 6-fold
P pm ok/24
106.0 100.0 137.5 139.3
tions (P > 0.05, paired I test). Urinary zinc excretion before therapy averaged 401 zg/24 hr (Table 1), again similar to previously reported values (7). No significant difference was found when comparing the change in urinary zinc excretion after 2 weeks of Lhistidine and placebo therapy (+ 186 versus + 137, respectively, P > 0.05), although there was a significantly greater urinary zinc excretion after 1 week of L-histidine compared to placebo (+ 234 tg/24 hr versus + 126, P < 0.05, paired t test).
hiatidine
Initial
nmole/mI
after placebo for albumin-bound zinc concentrations, percentage of albumin-bound zinc, or
Urinary
zinc excretion
and
in the
normal
kidney.
Total
zinc,
albu-
min-bound zinc, and a2-macroglobulinbound zinc concentrations in serum were also not different between L-hlstidine and placebo treatment periods. Urinary zinc excretion increased after 1 week but not after 2 weeks of L-histidine
therapy.
In the
absence
of a con-
comitant increase in urinary histidine week of L-histidine, the mechanism marginal
but
statistically
significant
after 1 for this increase
in urinary zinc is not clear. The proposed mechanism for the previously reported anorectic properties or oral Lhistidine involves the removal of zinc from albumin
binding
sites
by histidine
excretion of small histidine the urine to result in acute Histidine was chosen (3) on vitro experiments in which found to be the most effective removing zinc from human (13).
Concentrations
of
and
rapid
zinc moieties in zinc loss (3). Lthe basis of in histidine was amino acid for serum albumin
histidine
approxi-
SCHECHTER
1014
mately 10-fold greater than serum concentrations achieved in the present study were found necessary to have any effect on albumin-bound zinc even under these in vitro
conditions (13). It is possible tidine at doses greater than sorbed and not metabolized, serum histidine concentrations reach
pete
the
theoretical
level
that oral L-his4 g/day, if abmight result in sufficient to
necessary
AND
PRAKASH 3.
intake 1977. HENKIN,
5.
SCHECHTER,
to com-
with the albumin. The absence in urinary histidine excretion in the present study indicates that the Km for histidine reabsorption in the kidney was not exceeded by the doses employed. Again, it is possible that higher doses of histidine might exceed this threshold. No results of serum or
V.
histidine
reported
clinical
taste
smell
Although
been ities
concentrations
in previous and
have studies. disturbances
been have
reported
in conditions
are not intake.
in association with abnormalzinc status in a variety of clinical (14-17), such sensory disturbances invariably linked to changes in food In a study of 103 patients with taste only 26% reported weight loss and,
disorders, in the absence
of dysgeusia,
weight
loss
was
infrequent (14). It is apparent that evidence is still lacking to associate zinc homeostasis with appetite and food intake in man. Our attempt to modify zinc balance and induce anorexia in nonobese volunteers using oral L-hlstidine was unsuccessful. We have no reason to suspect that L-histidine if administered sults suggest, doubtful use
would have a different to obese individuals.
therefore, in clinical
action Our re-
6.
Some
R. I., H. R.
KEISER
D.
AND
BRONZERT.
Histidine-dependent zinc loss, hypogeusia, anorexia and hyposmia. J. Clin. Invest. 51: 44a, 1972. 2.
HENKIN,
R. I., B. M.
BRoNznnT. A syndrome Neurol. 32: 745, 1975.
PATrEN,
P. K.
of acute
RE
zinc
AND
D. A.
loss.
Arch.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
H.,
effects
J. J.
AND
11.
of
acids.
PI5AN0.
FREEMAN,
excessive
Proc.
SCHLIENGER,
Fluorescamine
intakes
Soc. Exptl.
R. M.,
P. R.
AND
of
Biol.
administration on zinc J. Nutr. 30: 523, 1977. 12. HENKIN, R. I. Metal-albumin-amino tions: chemical and physiological In:
New
13. GiRoux, zinc
among
chem.
14.
York:
E. L.,
ZERT,
M. S.
AND
serum
Biophys.
SCHECHTER,
121: 695,
lnfluence
metabolism
of
in the
acid interacinterrelationships. Interactions, edited by M. FriedPlenum Press, 1974, p. 299.
Protein-Metal
man.
indispensable
Med.
TAYLOR.
histidine rat. Am.
Acta
R. I. 273:
P. J., W. T. RAFF
HENKIN.
albumin
AND
hypogeusia:
a description
single-blind
study
Neurobiol.
HENKIN,
J. L.
AND
NAKAMURA,
amino 1966.
with
and
64,
Competition amino
1972.
D. A.
FRIEDEWALD,
R. I.
HENKIN.
of the zinc
for
Bio-
acids.
sulfate.
BRON-
Idiopathic
syndrome Internat.
and
a
Rev.
(Suppl. 1): 125, 1972. K. 1., P. J. SCHECHTER AND R. I. HENKIN. Hypogeusia, anorexia, and altered zinc metabolism following thermal burn. J. Am. Med. Assoc. 223: 914, 1973. 16. SMITH, F. R., R. I. HENKIN AND R. B. DELL. Disordered gustatory acuity in liver disease. Gastroenterology 70: 568, 1976. 17. SCHECHTER, P. J., AND R. I. HENKIN. Abnormalities of taste and smell after head trauma. J. Neurol. Neurosurg. Psychiat. 37: 802, 1974. 15.
1.
P. J., E. L. GIROUX, A. SJOERDSMA.
HOENIG
derivatives ofhistidine, histamine and certain related imidazoles: unique fluorescence after heating in acid. Arch. Biochem. Biophys. 177: 334, 1976. 7. GIROUX, E. L., M. DURIEUX AND P. J. SCHECHTER. A study of zinc distribution in human serum. Biomorgan. Chem. 5: 211, 1976. 8. CHESTERS, i. K., AND J. QUARTERMAN. Effects of zinc deficiency on food intake and feeding patterns of rats. Brit. J. Nutr. 42: 1061, 1970. 9. WILLIAMS, R. B., AND C. F. Miu.s. The experimental production of zinc deficiency in the rat. Brit. .1. Nutr. 24: 989, 1970. 10. HARPER, A. E., R. V. BECKER AND W. P. STUCKI.
that L-histidine is of anorectic therapy.
References
of food 300: 321,
Distribution of serum zinc between albumin and a-macroglobu1in in patients with decompensated hepatic cirrhosis. Europ. J. Clin. Invest. 6: 147, 1976.
increase
urinary
aspects in the control Ann. N.Y. Aced. Sd.
R. I. Zinc dependent control offood intake, taste and smell function. Proceedings of the 3rd International Symposium on Trace Element Metabolism in Man and Animals, edited by M. Kirchgessner, Freising-Weihenstephan, Arbeitskreis f#{252}r Tierern#{228}hrungsforschung Weihenstephan, 1978, p. 190.
4.
for zinc
of an
R. I. New and appetite.
HENKIN,
COHEN,
J. Schechter,2
M.D.,
Ph.D.
and Nellikunja
J. Prakash,
Ph.D.
ABSTRACT
L-Histidine, 4 g/day in gelatin capsules, was administered orally to eight normal volunteers for 2 weeks in a double-blind, balanced, crossover study with 2 weeks of placebo treatment. Body weight, serum and urinary zinc and histidine concentrations, as well as subjective ratings of appetite, taste and smell perception, and food intake were monitored. L-Histidine therapy had no significant effect on appetite, taste and smell perception, food intake, or body weight. Similarly, no effects were observed on total serum zinc, albumin-bound zinc or a,-macroglobulinbound zinc concentrations, or on urinary histidine excretion. Serum histidine concentrations increased with therapy. Urinary zinc excretion was increased significantly after 1 week, but not after 2 weeks of L-hlstidlne therapy. It can be concluded that oral L-histidlne, at the dose used, has no value as an anorectic agent. Am. I. Clin. Nut,. 32: 1011-1014, 1979.
Oral administration of large doses of Lhistidine to man has been reported to produce alterations in zinc metabolism accompanied by anorexia, taste and smell dysfunction, mental changes, cerebellar dysfunction, and loss of body weight (1-3). These signs and symptoms have been attributed to acute body loss of zinc since they correlated with a decrease in serum zinc concentrations and elevations in urinary zinc excretion and were rapidly reversed following oral administration of zinc ion, despite continued L-histidine administration (2, 3). The mechanism proposed for this syndrome involves a stripping of zinc from normal binding sites on serum albumin by histidine and excretion of small molecular weight histidine-zinc ligands in the urine (2). The loss of appetite induced by oral Lhistidine administration has been used in open studies in nonobese and obese subjects (1,3,4) to produce controlled weight loss and has been proposed as a new approach to clinical appetite control. The present doubleblind study was undertaken to attempt to verify the previous uncontrolled studies and to investigate the possible efficacy of oral Lhistidine as anorectic therapy in man. TheAmerican
Journal
of Clinical
Nutrition
32: MAY
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
1979,
Methods Eight male volunteers (ages 32 to 38) were used as subjects. The subjects were free of any chronic diseases, not under therapy with any medication, followed a normal dietary regime and had not gained or lost more than 5 kg within the 6 months before the start of the study. The mean body weight of the subjects before treatment was 71.6 kg (range: 59.8 to 80.5). All subjects were studied during the same 4-week period during the months of September and October. L-Histidine was prepared in capsules. Each capsule was formulated to contain L-histidine base, 250 mg, with lactose (80 mg) and hydrogenated castor oil (15 mg) as excipients. Placebo capsules with an identical appearance were prepared using 330 mg lactose and hydrogenated castor oil (15 mg). L-hiStidifle and placebo capsules were administered in a double-blind balanced, cross-over design. Each subject was randomly assigned to one of two groups. Group I (four subjects) received 14 days of placebo followed by 14 days of L-histidine (4,g/day); group II (four subjects) received 14 days of L-histidine followed by 14 days of placebo. Four capsules were taken 4 times per day with 200 ml water, before breakfast, at 10 AM, 3 PM, and at bedtime. This number of capsules (16 size 1 capsules per day) was considered maximal for subject compliance with the protocol and for practicalness. No attempt was made to modify the subjects
normal
purpose
and design
of the study.
the Centre
de Recherche
‘From
diet
although
all
were
Merrell
aware
International,
16, rue d’Ankara, 67084 Strasbourg Cedex, France. 2Author to whom requests for reprints should addressed. pp.
1011-1014.
Printed
in U.S.A.
the
of
be
1011
1012
SCHECHTER
Subjects scales each place along length): No
AND
were instructed to complete visual analog evening by placing an X at the appropriate four lines (each of which measured 10 cm in
Body
to eat
today
weight
The day
desire
PRAKASH
changes
course
Ravishingly
i
Food tasted like paper today
in body
for each hungry
today
A)
(line
B)
(line C)
I
Smells and taste today had more pleasant qualities than usual
Ate less today
I-
I
Ate more
Line A was designed to evaluate appetite; line B, to detect the presence of hypogeusia and/or hyposmia; line C, dysgeusia and/or dysosmia and line D to estimate food intake. Responses were recorded as the distance of the X (to the nearest one tenth centimeter) from the lefthand limit of the line. Biochemical
determinations
Blood and 24 hr urinary samples were collected from each subject immediately before starting the study and at weekly intervals thereafter. Blood was sampled approximately 1 hr after a dose in the fasted state (except for the ingestion of the four capsules plus water). Serum was obtained with precautions to avoid zinc contamination as previously described (5). Urine was collected in plastic containers without preservative. Histidine concentrations were estimated in serum and aliquots of 24-hr urine samples using the method of Nakamura and Pisano (6). Urinary and total serum zinc, as well as albuminbound zinc and az-macroglobulin-bound zinc in serum, were estimated using the procedures previously described (7).
Results Subjective
evaluation
A comparison of the responses of each subject on the same respective day of each course did not reveal any difference (P>> 0.05, paired t test) on any day for either lines A, B, C, or D between placebo and L-hiStldlfle treated groups. In seven of eight subjects no difference between placebo and L-hlstldlne was found when average values for each line over the entire 14-day courses were considered (t test, 2-tailed). In one subject (subject II) the mean values recorded for line A (3.8 cm) and line D (3.8 cm) during placebo therapy (course 2) were significantly lower (P < 0.005) than those during the L-hlStichne course (4.9 and 4.9, respectively). No differences in lines B or C were noted in this subject.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
each 14in Table
(line
P
usual
over
are given
I could taste and smell food especially well today
Some smells and tastes today had bizarre, unpleasant quality than
weight
subject
today
than
usual
1. No difference and L-histidine test). Serzrn,z
and
(line
D)
was found between therapy (P >> 0.05,
urinary
placebo paired I
histidine
Compared to pretreatment values, the mean change in serum histidine concentration after 1 week of L-histidine therapy was significantly greater (P < 0.001, paired I test) than the change after 1 week of placebo (+ 49.2 tmoles/ml versus 4.7). A similar, al-
though
smaller
change,
was
present
(Table
when values after 2 weeks of each course considered (+ 33.7 smo1es/ml versus
-
1)
was 85,
P < 0.05).
Urinary free histidine excretion, however, failed to differentiate between subjects taking L-histidine and those taking placebo. Compared to pretreatment values, the increase in urinary histidine after either 1 or 2 weeks of therapy was not significantly different between placebo and L-histidine treated subjects (P>> 0.05, paired I test). Serum
and
urinary
zinc
Before the onset of any therapy, the mean total serum zinc of the subjects was 88.5 sg/ 100 ml (Table 1); a value in agreement with those we have previously reported for normal subjects (5, 7). The differences between pretreatment total serum zinc concentrations and those after 2 weeks of L-hiStidine therapy were not different from values after 2 weeks of placebo (P>> 0.05, paired t test). Pretreatment mean concentrations of albumin-bound zinc and armacroglobulinbound zinc were 60.3 g/l00 ml (68.9% of total zinc) and 27.3 tg/100 ml, respectively. No significant differences were found between changes after L-histidine treatment and
ZINC
TABLE
METABOLISM
IN MAN
1013
1
Body weight change, serum histidine and zinc concentrations, and urinary histidine treatment with placebo (P) for 2 weeks and L-histidine (H), 4 g/day for 2 weeks Subject
Age
Body wt
Treatment order
n,t,al
Serum A
P
H
Initial
kg
1 II III IV V VI VII VIII
38 38 34 37 35 32 35 33
P-H H-P H-P P-H H-P P-H H-P P-H
Means
histidine P
80.5 74.3 75.7 70.9 62.7 59.8 79.6 69.5
+0.1 -0.4 +0.1 +1.6 +0 .4 +0.1 +0.4 0
+0.3 +0.8 0 -2.1 +0 .6 +0.2 +1.1 +0.6
71.6
+0.3
+0.2
a2-macroglobulin-bound
H
90.5
95.3 107.5 100.0
84.8 94.0 100.0 73.5
93.5 95.0 102.5 90.0 96.8
zinc
1465 710 1459 1540
97.0
98.5
1786
84.5 84.8 87.5 88.3
227.5 147.8 87.3 130.5
922 2135 1459 1435
concentra-
Discussion
Decreased food intake and weight loss are invariable features of zinc deficiency in rats (8, 9). The effects of L-histidine, however, on appetite and body weight of rats are unclear. The addition of excess L-histidine to the diet of rats has been reported to depress growth rate (10). In another study, however, chronic oral administration oflarge doses of histidine to rats had no effect on weight gain despite a increase
in urinary
zinc
excretion
(11). The administration of L-histidine in large doses to man in uncontrolled studies has been reported to produce an experimental, reversible zinc deficiency accompanied by taste and smell abnormalities, loss of appetite, and decreased food intake (2-4). A dose of 4.2 g of L-hlstidlne was said to produce anorexia within 4 days at which time there was no
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
Total H
Initial
hr
1460 846 944 1781
pg
1509 2000 1365 1008
Urinary
H
P pg /24
104 104 100 64 88 100 116 108 92 104 104 96 99 98
92 84 84 88
Zn
Initial
ml
108 92 96 96
76
962 2150 1714 1712
Zn
P lilY)
96 92 84 92
492 2987 1414 1267 1644 1231
Serum
after
637 284 479 246 353 418 456 333 401
H hr
850 980 478 560 480 480 366 352 281 577 760 644 577 598 511 502 538 587
alteration in urinary zinc excretion or serum zinc concentrations (3). With greater doses of L-histidlne, urinary zinc excretion is increased and serum zinc concentrations decreased (2, 12).
In the present of oral
double-blind
L-histidine,
petite,
subjective
study
4 g/day,
no effect
is found
on
ap-
taste and smell perception, in normal volunteers. Serum
or body weight histidine concentrations are elevated after oral L-histidine administration. No significant change in urinary free histidine excretion can be found after histidine treatment corn-
pared to placebo treatment, consistent with the efficient resorptive mechanism for amino acids
3- to 6-fold
P pm ok/24
106.0 100.0 137.5 139.3
tions (P > 0.05, paired I test). Urinary zinc excretion before therapy averaged 401 zg/24 hr (Table 1), again similar to previously reported values (7). No significant difference was found when comparing the change in urinary zinc excretion after 2 weeks of Lhistidine and placebo therapy (+ 186 versus + 137, respectively, P > 0.05), although there was a significantly greater urinary zinc excretion after 1 week of L-histidine compared to placebo (+ 234 tg/24 hr versus + 126, P < 0.05, paired t test).
hiatidine
Initial
nmole/mI
after placebo for albumin-bound zinc concentrations, percentage of albumin-bound zinc, or
Urinary
zinc excretion
and
in the
normal
kidney.
Total
zinc,
albu-
min-bound zinc, and a2-macroglobulinbound zinc concentrations in serum were also not different between L-hlstidine and placebo treatment periods. Urinary zinc excretion increased after 1 week but not after 2 weeks of L-histidine
therapy.
In the
absence
of a con-
comitant increase in urinary histidine week of L-histidine, the mechanism marginal
but
statistically
significant
after 1 for this increase
in urinary zinc is not clear. The proposed mechanism for the previously reported anorectic properties or oral Lhistidine involves the removal of zinc from albumin
binding
sites
by histidine
excretion of small histidine the urine to result in acute Histidine was chosen (3) on vitro experiments in which found to be the most effective removing zinc from human (13).
Concentrations
of
and
rapid
zinc moieties in zinc loss (3). Lthe basis of in histidine was amino acid for serum albumin
histidine
approxi-
SCHECHTER
1014
mately 10-fold greater than serum concentrations achieved in the present study were found necessary to have any effect on albumin-bound zinc even under these in vitro
conditions (13). It is possible tidine at doses greater than sorbed and not metabolized, serum histidine concentrations reach
pete
the
theoretical
level
that oral L-his4 g/day, if abmight result in sufficient to
necessary
AND
PRAKASH 3.
intake 1977. HENKIN,
5.
SCHECHTER,
to com-
with the albumin. The absence in urinary histidine excretion in the present study indicates that the Km for histidine reabsorption in the kidney was not exceeded by the doses employed. Again, it is possible that higher doses of histidine might exceed this threshold. No results of serum or
V.
histidine
reported
clinical
taste
smell
Although
been ities
concentrations
in previous and
have studies. disturbances
been have
reported
in conditions
are not intake.
in association with abnormalzinc status in a variety of clinical (14-17), such sensory disturbances invariably linked to changes in food In a study of 103 patients with taste only 26% reported weight loss and,
disorders, in the absence
of dysgeusia,
weight
loss
was
infrequent (14). It is apparent that evidence is still lacking to associate zinc homeostasis with appetite and food intake in man. Our attempt to modify zinc balance and induce anorexia in nonobese volunteers using oral L-hlstidine was unsuccessful. We have no reason to suspect that L-histidine if administered sults suggest, doubtful use
would have a different to obese individuals.
therefore, in clinical
action Our re-
6.
Some
R. I., H. R.
KEISER
D.
AND
BRONZERT.
Histidine-dependent zinc loss, hypogeusia, anorexia and hyposmia. J. Clin. Invest. 51: 44a, 1972. 2.
HENKIN,
R. I., B. M.
BRoNznnT. A syndrome Neurol. 32: 745, 1975.
PATrEN,
P. K.
of acute
RE
zinc
AND
D. A.
loss.
Arch.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/5/1011/4666325 by University of Glasgow user on 23 April 2018
H.,
effects
J. J.
AND
11.
of
acids.
PI5AN0.
FREEMAN,
excessive
Proc.
SCHLIENGER,
Fluorescamine
intakes
Soc. Exptl.
R. M.,
P. R.
AND
of
Biol.
administration on zinc J. Nutr. 30: 523, 1977. 12. HENKIN, R. I. Metal-albumin-amino tions: chemical and physiological In:
New
13. GiRoux, zinc
among
chem.
14.
York:
E. L.,
ZERT,
M. S.
AND
serum
Biophys.
SCHECHTER,
121: 695,
lnfluence
metabolism
of
in the
acid interacinterrelationships. Interactions, edited by M. FriedPlenum Press, 1974, p. 299.
Protein-Metal
man.
indispensable
Med.
TAYLOR.
histidine rat. Am.
Acta
R. I. 273:
P. J., W. T. RAFF
HENKIN.
albumin
AND
hypogeusia:
a description
single-blind
study
Neurobiol.
HENKIN,
J. L.
AND
NAKAMURA,
amino 1966.
with
and
64,
Competition amino
1972.
D. A.
FRIEDEWALD,
R. I.
HENKIN.
of the zinc
for
Bio-
acids.
sulfate.
BRON-
Idiopathic
syndrome Internat.
and
a
Rev.
(Suppl. 1): 125, 1972. K. 1., P. J. SCHECHTER AND R. I. HENKIN. Hypogeusia, anorexia, and altered zinc metabolism following thermal burn. J. Am. Med. Assoc. 223: 914, 1973. 16. SMITH, F. R., R. I. HENKIN AND R. B. DELL. Disordered gustatory acuity in liver disease. Gastroenterology 70: 568, 1976. 17. SCHECHTER, P. J., AND R. I. HENKIN. Abnormalities of taste and smell after head trauma. J. Neurol. Neurosurg. Psychiat. 37: 802, 1974. 15.
1.
P. J., E. L. GIROUX, A. SJOERDSMA.
HOENIG
derivatives ofhistidine, histamine and certain related imidazoles: unique fluorescence after heating in acid. Arch. Biochem. Biophys. 177: 334, 1976. 7. GIROUX, E. L., M. DURIEUX AND P. J. SCHECHTER. A study of zinc distribution in human serum. Biomorgan. Chem. 5: 211, 1976. 8. CHESTERS, i. K., AND J. QUARTERMAN. Effects of zinc deficiency on food intake and feeding patterns of rats. Brit. J. Nutr. 42: 1061, 1970. 9. WILLIAMS, R. B., AND C. F. Miu.s. The experimental production of zinc deficiency in the rat. Brit. .1. Nutr. 24: 989, 1970. 10. HARPER, A. E., R. V. BECKER AND W. P. STUCKI.
that L-histidine is of anorectic therapy.
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Distribution of serum zinc between albumin and a-macroglobu1in in patients with decompensated hepatic cirrhosis. Europ. J. Clin. Invest. 6: 147, 1976.
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urinary
aspects in the control Ann. N.Y. Aced. Sd.
R. I. Zinc dependent control offood intake, taste and smell function. Proceedings of the 3rd International Symposium on Trace Element Metabolism in Man and Animals, edited by M. Kirchgessner, Freising-Weihenstephan, Arbeitskreis f#{252}r Tierern#{228}hrungsforschung Weihenstephan, 1978, p. 190.
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for zinc
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HENKIN,
COHEN,
