ENZYMATIC
PATTERNS
DURING
DEVELOPMENT
An
Approach
to a Biochemical
Definition
of Immaturity
E.
Mead
Johnson
Award
Address
By Norman Kretchmer, M.D., Ph.D.
Departnmcnt of Pediatrics, New York Hospital-Cornell Medical Center
Presented at the Annual Meeting of the Academiiv, October 21, 1958.
These investigations have been supported continuously by the National Instittmte of Arthritis and Metabolic Diseases of the National- Institutes of Health, Public Flealth Service (A-389) and the Kidney 1)isease Foundation of New York, Inc., and in part by the Association for Aid to Crippled Childremi, New York Ileart Association, Ruth Papier Nephrosis Foumiolation of New Jersey amid the Damon Runyon Niemonial Fund.
ADDRESS: 525 East 68th Street, New York 21, New York.
PEDIATRICS, March 1959
606 I would like to express my gratitude to you,
the Amenicami Academy of Pediatrics, for
select-ing me for an E. \-Iead Johnson Award. I ac-cept the homior with humility because mio scien-tific work is accomplished without inspiration from teachers amid other investigators, and without actual participation of mamiy
col-leagues. I appreciate this opportunity to
ac-knowledge publicly those individuals who have been amid are particularly imiflumential imi my progress.
Dr. Jean Oliver, the man to) whom I owe my entry into medicimie amid pediatrics, vith great
effort imistillecl in mne an everlastimig apprecia-tiomi for the imiseparable relationship between
structure and function. Fortumiately, I have
re-maimied in close contact with Dr. Oliver throughout the ‘ears, contimnmallv reaping
bemie-fits from his adivice and influence.
I conceived of fimmiction as omil’ cellumlar anal molecular umitil Dr. Henry L. Barnett imitro)-dumced rime to organ functiomi, especially in rela-tion to the young imidividimal. In addition, he fostered in me an interest in the broader
as-pects of pediatrics, amid since that time has
been available constantly for imitimate exchange
and crystalhizatiomi of ideas.
I am indebted particularly to Dr. S. Z. Le-vimie for leading me imito the field of biologic developmemit amid imisistimig that my time be divided h)etveemi climiical pediatrics amid the laboratory. Dr. Levine has always emphasized that ideas, philosophies and problems origimiat-ing in the ward or chimiic can and should be
considered imi the laboratory. His subtle
direc-tion has gumided me towards the integratiomi 0)f climiical amid investigative pediatrics, and his
conceptual kmiowledge of medicimie has beemi an invaluable stimiiulus to inc.
Finally, without the loyal, unselfish amid umi-tiring help o)f Miss Helen -IcNamara, it would have been exceedimigl’ difficult to have ac-complishied these stud!ies.
T
HE FOLLOWING is a review of the varioussteps we have taken in our attempt to
arrive at a biochemical interpretation of
immaturity. About 6 years ago, Dr. Levine
and I discussed his extensive ol)servations
concerning the role of vitamimi C in the
complete metabolism o)f tyrosine in
prema-tune infants. Originally, Dr. Levin&t
oh-served that if the d!iet of the premature
in-fant was not supplemented! with ascorbic
acid, tyrosine and
p-hydroxyphenylpynui-vate appeared in the umnine, and addition of
ascorbic acid caused these substances to
disappear. Later it was shovn in vitro that
ascorbic acid was required for complete
metabolism of tyrosine. We have since
found that large amounts of ascorbic acid!
will activate the enzyme,
p-hyc!noxyphienyl-pyruvate oxidase, from liver of premature
infants on fetal animals. This observation is
analogous to the findings in vivo4 that pre-mature infants required as much as 50 mg of vitamin C for alleviation of the tyrosy-lunia. These data provided an impetus for
investigatio)mis into) the mechanism of action
of vitamin C in tyrosyhumnia. From the initial
Jt
p-HYDROXYPHENYLPYRUVATE
PHENYLPYRIJVATE 2
3
I
1
#{176}2
FUMARATE
+ ACETOACETATE
AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 607
E-PHENYLALANINE
-i->
TYROSINE
4
2
1. Tyrosine
Oxidizing
System
2.
Tyrosine
Transaminase
3.
p-.OHphenylpyruvate
Oxidase
4.
Phenylalanine
Hydroxylase
5.
Phenylalanine
Transaminase
HOMOGENTI
SATE
Fic. 1. Pathways of phenylalanine and tyrosine metabolism.
pathways, some of which will be discussed.
A program considerably broader than
onig-inahly intended has developed from these observations. As yet the results do not
com-prise a complete story but they do permit
formulation of some conclusions.
The discumssion may begin with a
dia-grammatic description of the pathways for
metabolism of phenylahanine and tyrosine, as shown in Figure 1. Every reaction in this scheme involves at least one enzyme and the name and the position of each is
speci-fled. The tyrosine oxidizing system,
desig-miated as 1, includes all enzymes essential to the degradation of tyrosine. The triple arrow between homogentisate and fuma-rate-acetoacetate is designed to indicate the probability of at least three
intermedi-ate steps. Each enzyme requires cofactors,
i.e., coenzymes or activators for optimum activity. These will be discussed as required
for elucidation of the present report. The
biochemical intricacies of this pathway have been recently reviewed extensively.9
Each enzyme noted has been studied in
the livers of both fetal and adult animals
and the results are shown in Figure 2.
Under standard conditions the individual
enzyme shows considerably less activity in fetal than in adimlt tissue.1#{176} Livers from premature infants were obtained at nec-ropsy and showed activities comparable to
those with tissue from fetal rats.11
The tyrosine oxidizing system, tyrosine
transaminase, and phenylalanine
hydroxyl-ase show minimal activities in fetal liver but
p-hydroxypiienylpynmvate oxidase from
tis-sue of fetal animals has an activity about
30% of the level in adimlt livers. The lack of activity observed could be due to the
presence of an enzymatic inhibitor or
ab-sence of an activator in the livers of
pre-matumre infants and fetal rats; consequently
experiments were designed to test this
hiy-pothesis, utilizing the tyrosine oxidizing
sys-tem.10’ Thus homogenate of a liver from a premature infant was added to that from an adult and there was no depression or elevation of activity observed. A
prepara-tion of adumlt liver was boiled and
ultra-filtered and addition of these nonprotein extracts failed to activate the preparation from liver of the premature imifant. Similar
extracts from a liver of a premature
in-fant did not inhibit activity of enzyme from
ascor-100-
-50
-U
PREMATUREINFANT
RAT FETUS
--ADULT TYROSINE
OXIDIZING SYSTEM
p-OHPHENYLPYRUVATE OXIDASE
Fmc. 2. Activity of enzymes of plmeny’lmlanine and tyrosine netabolisnm in tilL. liver of prnm11ttt1rn
infants and rat fetums.
PHENYLALANINE
HYDROXYLASE
608 ENZYNIATIC PATTERNS
V
0
>%
>
0
0
C
TYROSINE TRANSAMINASE
bic acic! dud miot stimulate the tyrosine
oxidizing system.
From these data it became apparent that slight causal imiformatiomi coumlc! be gainech fm om studies of the over-all system, and so the investigation was extended to a survey of inohividual emizymatic reactions. These observations demonstrated that three differ-emit types O)f c!eficiency of enzymatic
activ-ity may occtmr in peninatal life: 1) absence
of emizyme; 2) necessity for an activator; amid! 3) absemice of one enzyme in a multi-enzyme system.
An examnple of deficiemicy of emizymatic
activity clue to the absence of enzyme is sho)wn by the results with tyrosine trans-aminasem#{176} (Fig. 3), an enzyme which has
sl)ecificity’ so)lely for tyrosine.’2 This enzyme reqimires -ketoglumtanate as the aminO-gro)ump
acceptor amid a coenzyme, pynidoxal phos-phate, for maximumm activity. Activity of the enzyme was ascertainec! from the amount of p-hychroxyphienylpyruivate prodhulced!
un-cher co)ntrolled conditions. Figure 3 is
de-nived from a sample experiment showing
the effect o)f increasing concentration of
pyrid!oxal ihsi1iate omi the activity of
tyrosine transamninase in livers from a
2-houmr-olc! and a 10-hour-old rat. The
dif-fenemice in activity with age is apparent, I)ut imicrease in coenzyme did not result imi a proportionate increase in enzyme activity in liven from the youmiger animal. In
addi-tiomi, excessive amounts of the amino-group
acceptor, -ketoglumtarate, failed to increase
activity in very young animals. However, the ado!ition of niumch larger amounts of tissue preparations did result in
demon-strable enzyme activity, showing that some
enzyme was present imi the liver of the yoimnger animal. This nesimlt was interpreted to) imiclicate the iiresence in tissume from very young animals of tii almost negligible
amount of apoenzynie (protein portion of the enzyme) and therefore excessive
addi-tion of nomi-protein components of the
sys-tem could not influence activity of the
enzyme. Thums, lack of productiomi of the
protein portion of a specific enzyme is one
possible mechanism that can lead to lack of enzymatic activity in tissues of the very young organism.
p-Hydroxyphienylpynuvate oxidase of fe-tal liver illustrates a contrasting situation in which there is a requmirenient for large
amounts of activator11 (Fig. 4). The activity
of this enzyme is measured by utilization of p-hydroxyphenylpynumvate and also by consumption of molecimlan oxygen. The re-action is aerobic and requmines ascorbic acid on a suitable substitute, such as dhchloro-phenolindophenol.’’ Whemi 1 mg of ascorbic
acic! (an amount sufficient to give maximum
200-
50-0
10
hrs. of
age
2 hrs.
of
age
I I
30
60
jig.
Pyridoxal
Phosphate
90
AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 609
4-.
>1
4-.
4-0
(l)0.
0
Cci
(no-.
go-.
‘-9
cDo-C#{149}
I-Tyrosi ne
Pyridoxol
Phosphate
0<-
kefoglufarafe
p-OHPP
Fir.. :3. Relatiomiship l)etweemi concentration of pridoxal phosphate and activity of tyrosine transamiiinase.
in liver of the child is obtained. When either preparation is boiled or when no enzyme is added, there is rio utilization of p-hydroxyphienylpynumvate. Homogentisate was determined in selected experiments amid an amount was detected equivalent to the p-hydnoxyphenylpyruvate utilized. As
shown in Figure 4, increasing concentration of ascorbic acid stimulated activity of the
enzyme until maximum activity was finally
reached. Dichlorophenolindophenol coimld
activate ti-me enzyme but activity was not
maxinial. Resumlts similar to) these obtained! with liver of premature infant were oh-served with the enzyme derived from livers of fetal rats or rabbits. It was possible that young tissues, in particular, destroyed
as-corhic acid! bumt further imivestigatio)ns imic!i-cated! that ascorbic acid was miot inactivated! either by oxidation or enzymatic action by liver from a Iirematumre infant. As it had
been shown that catalase was also
prob-ably required for the conversion of p-hy-d!roxyphenylpynumvate to) homogentisate,
cat-alase was added to enzyme from liver of a
premature infant, but no imicrease in p-hiy-droxyphenylpyruvate umtihization resulted. These data probably imidicate that time en-zyme, p-hydnoxyphenylpynusvate oxidase, is
present in fetal tissue but that very large
amounts of ascorbic acid are required! for
activation. The ascorbic acid may act to
remove an inhibitor of enzymatic activity.
I.
I.
0.
5
10
15
Fmc. 4. Effect of imicreasing ascorbic acid on activity of p-hydroxyphenylpyruvate oxidase of liver.
TABLE I
Ad”rmVITY OF PHENYLALANINE llYDIloxYI..vsF: IN TIlE
LmvEmo OF ADULT AND FETAL R.BnITs
. Tyrcsine Frn:ed
Preparation
(.irno1/hr)
610 ENZYMATIC PATTERNS
a)
4-0-.
a-0
0.
mg.
Ascorbic
Acid
Child
Premature
Infant
Boiled
Enzyme
Enzyme
02
p-OHPP
>Homogentisate
Ascorbic
Acid
responsible for deficient activity of an
en-zyme, that of lack of one enzyme in a
two-enzyme system, is exemplified by
phenyl-alanine hydroxylase,’’ ‘ the enzyme
re-quired for conversion of phenylalanine to
tyrosimie. The data in Table I were
oh-tamed with livers from rabbits, but results
were similar vith preparations from rat,
pig and man. As shown in Table I,
phenyl-alanine hydroxylase consists of at least two mms Fraction I, found only in liver, and Fraction II, found in all tissues exam-med. Fraction I is extremely labile and very difficult to work with; Fraction II is qumite stable. Separately Fraction I or Frac-tion II shiovs only slight ability for
hy-droxylation of phenylalanine, butt when
addled together the mixture is very active.
Phenylalanine hydroxylase from the liver of the fetal rabbit will form only minimal
Adult liver (1.43
Fetal liver 0.07
Fetal liver and Fractiomi I ().4 Fetal liver and Fraction II 0.05
Fraction I 0.(13
Fraction II 1)
1+11
TPN1I+II+Q+plIeII\’lalanine---+TPN + H2()
+tyrosine.
quantities of tyrosine. When Fractiomi I isolated from adult rat liver is added to fetal liver, there is an elevation in activity
2
-lB
I
2
3
4
5
6
7
8
Days
AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 611
FIG. 5. Patterns of enzymatic activity during development.
the addition of Fraction II has no effect. Thus, Fraction I is probably lacking in fetal
liver but Fraction II is present.
In summary, three different causes for lack of specific enzymatic activities in fetal tissue have been discumssed: First, an actual lack of enzyme protein, as with tyrosine
transaminase; second, the presence of
seem-ingly adequate concentrations of the pro-tein portion of an enzyme, but an inordinate and unexplained requirement for
nonpro-tein activators, as in the case of
p-hydroxy-phenylpyruvate oxidase; and finally, the
lack of one or more of the individual
en-zymes in a multi-enzyme system, as in the
instance of phenylalanine hydroxylase.
These experiments provided an
under-standing of the basis for some deficiencies
O)f enzymatic activity at a particular stage in early life. Information was still lacking as to the unique biochemical events leading to the complete development of enzymatic activity. As a first step in this direction, we
proceeded to investigate patterns of
en->
4-> 4-0
a)
> 4--0
a)
zymatic activity associated with postnatal
development of the organism.
Preparations were made from livers of
animals of different ages, starting during
fetal life (Fig. 5). Fetal age was
deter-mined with a maximum error o)f 1 day by
means of a vaginal smear from the female
the morning after the rats were mated. One
outstanding feature of these developmental
patterns is that the activity of one enzyme,
phenylalanine transaminase, reaches the
adult level 1 day before birth,1 then ex-ceeds that level, and gradually retumrns to the activity of the adult between 10 to 20 days after birth.
In contrast, activity o)f phenylalanine
hy-droxylase remains at a low level for 2 to 3
days following birth and then, during the
next few days, slowly reaches the activity
found in the adult.h
Most striking is the pattern of
dievelop-ment of tyrosine transaminase,2 which
suddenly exhibits activity 2 hours
.IOOO
I
0::;:;T I
-10
B
Days
10
20
30
5
Hours
AGE
10
IS
Adult
Days
--Kidney
-Liver
612 ENZYMATIC PATTERNS
Fmc. 6. Activity of glucose-6-phosphatase in liver and kidney during development of the rat.
activity, which is 2 to 10 times that
char-acteristic of the adult liver. Sixteen to twenty hours postnatally, the activity of this enzyme returns to that found with liver fromn the adhuilt animal.
Thus, there are real differences in the
developmental pattern among three
meta-bohically related enzymes. The physiologic significance o)f these differences is unknown, but the unprec!ictability of d!evelOl)mental
I1tterm1 for amiy omie enzymatic activity
he-comes strikingly apparent.
Incidentally, these data help to clarify
the ol)servatiomis of Levine et al.1t hat
p-hyc!roxyphenylpyruvate and! tyrosine are excreted in the urine o)f the premature
in-fant s’ho d!oes miot receive a dietary supple-ment of vitarnimi C. The d!evelopmental pat-tern for tyrosimie transaminase indicates that it is active SOOli after birth and tyrosine could l)e co)mivertedl to p-hydroxyphenyl-pyruvate. However, without ascorbic acid, p-hydroxpliemivIpvrimvate oxiclase would be
relatively inactive, accoumnting for the
ac-cumulation of p-hydroxyphenylpyruvate
and, consequmentl, tyrosine.
To retumrmi to the main discussion,
chiffi-cumlties multiply when one considers the d!evelopmemit in different o)rgamis of enzymes whicli ap)aremitly serve the same function. Resumlts illustrating this poimit with an
en-zymatic activity unrelated to tyrosine
me-tabohism are shown in Figure 6.21
Glucose-6-phospliatase activity in kidney shows a steady rise until the activity characteristic of the adult is attained!. In liver, activity of glumcose-6-phosphatase shows considerable change. The imiitial elevation in activity at birth is followed! within 24 hours by a further consic!erable increase and ultimately
approaches adult activity after 10 days of
life. When these data are plotted on the basis of nitrogen content, the curves main-tam their general shapes and relationships. Correlation betweemi these enzymatic changes and the physiology of these two organs is now being imivestigated!.
It voulc! appear that each enzyme may d’elop its activity in a different manner, related! in Part to its immed!iate environ-ment, the organ. Specific changes within the organ and peripheral to it must occur
for initiation of an increase in enzymatic
activity.
\Vhat are the possible “trigger” mech-anisms for development of enzymatic ac-tivity? A few years ago, we observedbo that there was an immediate postnatal spumrt of activity of the tyrosine oxidizing system in
the rat, which very shortly reached the
activity of the ac!umlt. It was postulated that
Newborn -12 Hours
AGE
A’dERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 613
C
a) 0 0.
>‘
.? E
U) C
INTACT
U
ADRENALECTOMY AT BIRTHADRENALECTOMY AT BIRTH
GIVEN HYDROCORTISONE
Fmc. 7. Effect of adrenalectomimy at birth on tvrosinc transanmimiase activity in rat liver.
hiorniones l)y time mother or the newborn,
attendant to stress at birth. Lin amid Knox22
recently showed! that activity of tyrosine
transaminase is considerably increased by
parenteral administration of adrenal
hor-mones and/or tyrosine to the adumlt rat. Omi the basis of these d!ata we uinc!ertook to study the relationship of ac!renal hor-mones to development of activity of
tyro-sine transaminase; the findings are shown
in Figure 7. Newborn rats were adrenal-ectomized immediately after birth, and the activity of tyrosine transaminase in their
livers was measured at intervals until 12
houmrs O)f age, the time of peak activity.20
The liver from the adrenalectomized ani-mal, 12 hours of age, had an activity
sum-ilar to) that of newborn animals and 20% of thie activity of the adult liver. When
hydro-cortisone was administered sumbcumtaneouisly
to the animal at the time of ac!renalectomy, the activity in the liver at 12 hours was
similar to) that of liver of the intact animal
O)f the same age. When ac!renalectomv was delayed until 2 houmrs after birth, results were erratic l)umt there was a tendency for the activity to be that in the liver of the intact animal.
These data indicate that there is an
im-mediate secretion of the adrenal glands,
vhich acts imi some ummiknowmi miiamimier to
stimulate forniation of enzvnie. \Vheii ac!renalectoniy iS d!elayed!,
tue
miiechamiismiifor emizyme formation apparently has
al-ready been initiated and is self-perpetuat-ing. It is O)f interest that the ad!aptive plie-nomenon of increased enzyme activity re-portec! I)y Lin and Knox, as a comisequemice of adiministration of tyrosimie and/or ac!remial hormone to adult amiimals, c!oes not occur
in animals less than 16 houmrs of age. Ne-meth23 mentioned! similar results with
trvp-tophan peroxic!ase in fetal guinea pigs.
Further evic!ence for the relationship of
hormonal function to enzymatic activity is
shown in Figure 8. These are data gathered
in our laboratory amid! are a repetition of work reported by Jost et a!. 21 The open
bars represemit the co)ncelitration of
ghyco)-gen in liver d!uning late fetal life imi rabbits. Soon after the twenty-eighth c!a’ of gesta-tion the concentration of glycogen normally
decreases rapid!lv. If the fetal ral)l)it is
c!e-capitated! in titero on d!ay 22 or 23 of
gesta-tion, the amoumit of glycogen imi the liver on
the twemity-eighith c!av is negligible. But
ost and Jacqumot2’ shlo\ved! that when the fetus is decapitated on day 25 or 26,
gly--cogen continues to accumulate as in the
25
22
23
24
25
26
27
28
30
Days
of
Gestation
614 ENZYMATIC PATTERNS
a)
C
a)-0’
0
E
0
Normal
fetus
a
Fetus
decapitated
on
22-23
day
of
gestation
Fmc. 8. Effect of intrauterine decapitation on glycogen storage in the liver of the fetal rabbit.
(d!ay 22 or 23) adrenocorticotropin (ACTH) is administered, then at 28 days, there is a normal amount of glycogen.
Thus, glycogen storage in fetal liver is
depenc!ent upon activity of the hypophysis
at a specific time. This endogenous
secre-tio)mi can be ac!equately replaced by
exoge-nous ACTH. Joint studies are in progress
with Professor Jost and his group to
de-termine the exact locus of action of
hypo-physeal hormomies on glycogen metabolism
in fetal life. Preliminary data indicate that
there may be increased degradation of
gly-cogen subsequent to decapitation.
DISCUSSION
It is apparent that certain enzymes are
inactive dumring fetal life and even in early
postnatal life. The developmental pattern
for an individual enzyme may be unique
and depend upon stimulation by specific
hormones at a critical time in the life of
the organism.
I have been primarily interested in two
major aspects of this problem: 1) basic
mechanisms for the development of activity of an enzyme; and 2) relationship of these phenomena to an understanding of imnma-turity.
In Figure 9 a sequence is proposed for mechanisms governing the appearance and regulation of enzymatic activity in an or-ganism. For proven examples of these events we are forced to borrow information
from microbial geneticists,2528 for they
have contributed invaluable observations necessary for understanding interrelations of heredity and development.
In a normal animal it can be assumed
that all genetic information necessary for
synthesis of a required quota of enzymes is present in the embryo. Following from this assumption there are three possibilities that coumld be responsible for lack of enzyme activity in the young animal: 1) enzyme is
not produced by virtue of some substance
repressing gene action;2 2) an incomplete
enzyme is produced that is inactive
be-caumse it is in the form of a proenzyme; and 3) enzyme is produmced in its complete form 1)ult i5 inactive as a result of an inhibitor
which must be removed. Figure 9 attempts
to depict these relationships.
Gene
A
Gene
B
me
Product
0-
Inhibition
x-
Activation
Enzyme
I
Produt
B
B
FIG. 9. Regulators of emizyniatic activity.
AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 615
life, or an increase in formation of enzyme
at a time immediately preceding the
ap-pearance of activity. These studies are now
in progress in our laboratory.19 As absence
of adrenocortical secretions has been shown
to result in deficiency of activity of
tyro-sine transaminase, it can be assummed that
adrenocortical hormones are required for
formation of the enzyme in a way as yet
not understood. In contrast, an enzyme can
be formed, but inactive, as shown with
p-hydroxyphenylpyruvate oxidase which
re-quires addition of ascorbic acid to activate
it.
However, there are many controls and
pacemakers which are required for
develop-ment to proceed in an orderly and
organ-ized fashion. Even after an enzyme is
ac-tive, the product formed may in turn
in-hibit further action of the enzyme. Product
inhibition is a well known biochemical
phe-nomenon; recently Gorini and Maas,3#{176}as
well as others,2528 have shown, with
bac-teria, that a product of enzymatic action
can inhibit directly at the gene site to
pre-vent further formation of enzyme. In this
manner the synthesis of the enzyme is
con-trolled. In some of the inborn errors of
metabolism in which the enzymatic defect
has been identified,3’ it is probable that
the disturbance is a result of a genetic
aberration leading to inactivity or absence
of a particular emizyme. It is readily
ap-parent that a great many observations must
be made before these processes are fully
comprehended.
The intact organism presents a different
group of problems not entirely genetic.
Levine et al.32 showed that when ACTH is
given to a premature infant whose diet is
not supplemented with vitamin C the
tyro-syluiria is alleviated. Preliminary datall
in-dicated that the probable site of action of
the ACTH is the renal tubule, causing a
decrease in tubular reabsorption of
tyro-sine and p-hydroxyphenylpyruvate. Still
an-other factor in the intact organism is the
actual amount of protoplasm available for
any particumlar function. Observations from
our laboratory indicate that cells from
the kidney of a fetal rabbit can transport
616 ENZYMATIC PATTERNS
from the kidney of an adumlt animal.
How-ever, there are fewer cells in the fetal
kic!-rie’ amic! totil fimnction o)f the orgami, when co)niparedl ‘itI-i the adult, is dimiiinishec!.
Superimposed 0)11 these pro)blemiis is die possil)ihty that a c!eflciency in enzyme ac-tivity couild leach to a lack of a metabohi-cally iniportamit produmct. For example, from
oumr chata, phenylalamiine hyd!roxylase is
in-active in liver of the prematumre infant, makimig tyrosine a chietary essential amnimio acid. Holt2 recemitly reported that histidine is an essential amimio acid for the infant bumt not the adhult. It is these potential nutni-tiomial aspects which may he important in the care o)f imifants bumt are less important
in titero, where niany numtritiO)nal substances
deficient in the fetus are supplied via thie
I)lice1itl.
\Vhat then is immatumrity? It is a word
c!efinec! as a lack of d!evelopment, bumt
in-herent in the concept of immatumrity mumst l)e the factor of time anc! the relationships of gemies, molecumles, cells and organs, sym-phonically arranged in an intact organism.
It is possible that these wic!e d!ifferences in
enzymatic c!evelopnient could! contribute to the variable vitality of premature infants and! their ability to adjust to a changimig enviro)Iimiielit. Immatumrity can be explained! and testec! for omi any or all of the bases c!iscussec!. ‘sIany of these metabolic d!efi-ciencies may be related to the fact that the imifant chiaminels niost of his effort towarc!s pn)teimi synthesis amid1 umltimately growth.
REFERENCES
1. Levine, S. Z., Marples, E., and Gordon,
H. H. : A defect in the metabolism of
aromatic amnimio acids in premature imi-fants: the role of vitamin C. Science,
90:620, 1939.
2. iclem: A defect in the metabolism of tyro-sine amid phenvlalamiine in prematuire in-famits. I. Identification and assay of in-termediary products.
J.
Clin. Invest.,20:199, 1941.
3. Ide1n: A defect in the metabolism of
tyro-sine amid phemi’lalanimie imi prematumre in-famits. II. Spontaneous occurrence amid
eradication by vitamin C.
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ESOPHAGEAL STRmCTURE FROM ACCIDENTAL INGESTION OF CLINITE5T1- TABLETS, C.
Zim-rnerman. (A.M.A.
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Dis. Child., 97:101, January, 1959.)Physicians should be aware that the accidental ingestion of Clinitest#{174} tablets, now
in commimon use for umrine analysis, can cause severe stricture of the esophagus because of their content of sodium hydroxide; perhaps the copper sulfate contained in the tablets may play a secondary role. The author adds a report of a case to 4 cases
