Vitamin A and Keratinization
William S. Logan, MD, Rochester, Minn
The effect of vitamin A on epidermal
dynamics is complicated by many vari-
ables, including species and regional
differences, which render compilation
of meaningful data difficult. Available
evidence indicates that vitamin A has a
predominantly proliferative effect on
mature rodent and human epidermis,
which may be dose-dependent. The
ancient concept of an "antikeratinizing
effect" is thus incomplete, though pos-
sibly not incorrect, when applied to
mammalian epidermis. Mucous meta-
plasia in response to excess vitamin A,
though consistently seen in embryonic
chicken skin, is not a feature of the
mammalian response, except in specif-
ic epithelia with "mucoid potential." The
precise mode of action at the molecular
level remains unknown, but lysosomal
labilization may be of major importance.
the early 1930s, with elucida¬
IN tion of its chemical structure, vi¬
tamin A became the first vitamin to
be well-characterized biochemically
and physiologically. Even prior to
this, the manifold effects of its
deficiency, both in man and labora¬
tory animals, had been accurately
described. Nevertheless, the precise
molecular role of vitamin A, as with
all of the vitamins, remains largely
unknown. It is the purpose of this
review to summarize the available
information on the mechanism of
action of vitamin A in one of its var¬
ied effects, the preservation of epi-
Accepted for publication Jan 4, 1972.
From the Mayo Graduate School of Medicine,
Rochester, Minn.
Reprint requests to Section of Publications,
Mayo Clinic, Rochester, Minn 55901.
Downloaded from www.archdermatol.com on November 12, 2010
CH,
.3
CH. ¿^ CH^
CH CH CH
Fig 1.-Vitamin A alcohol (retinol).
thelial integrity, with special refer¬
ence to the epidermis.
Physiology and Metabolism
Vitamin A is a fat-soluble, unsat-
urated long-chain isoprenoid that
exists in various chemical and iso¬
mer ic forms. The classic active form
that is usually found in mammalian
tissues is the all-trans alcohol vita¬
min A (vitamin A alcohol or reti¬
nol) (Fig 1). Physiologically impor¬
tant derivatives involve oxidation
esterification of the terminal alcohol
group to form vitamin A aldehyde
(retinal), vitamin A acid (retinoic
acid), and vitamin A esters (retinyl
esters). The carotenoids, especially ß-
carotene, are true provitamins of
vegetable origin which possess a dis¬
tinctive yellow-orange color. They
have no vitamin A activity in and of
themselves but are readily converted
into active vitamin A.
Dietary intake consists largely of
vitamin A, vitamin A palmitate of
animal origin, and carotenoids of
vegetable origin.1 These undergo
emulsification and hydrolysis within
the intestinal lumen (Fig 2), are con¬
verted to vitamin A palmitate in the
intestinal wall, and enter the lym¬
phatic system in conjunction with
chylomicra. On reaching the venous
system, the circulating vitamin A
ester is transported to storage de-
CH,3
|
pots, primarily the liver, where it is
C JCH.ÖH deposited as vitamin A palmitate.2
^CH As necessary, the stored vitamin A
palmitate is hydrolyzed by liver
enzymes and released into the circu¬
lation as vitamin A, complexed with
a specific a-globulin, for mainte¬
nance of normal blood levels and dis¬
tribution to the tissues to meet meta¬
bolic demands.2 The fate of vitamin
A in the tissues is poorly understood,
but it is worthy of mention that vita¬
min A acid represents the terminal
product of vitamin A oxidation. It
cannot be reduced to vitamin A or
vitamin A aldehyde, nor can it be
stored. It is probably disposed of
primarily via excretion in the bile as
the glucuronide.'1
or Which of the various forms of vita¬
min A represents the "active form,"
or whether there is a single active
form subserving all of the vitamin's
functions, is unknown, except for the
visual cycle where vitamin A alde¬
hyde is preeminent.
Molecular Function
The effects of vitamin A deficiency
are legion and center around (1)
growth impairment, (2) defective
bone growth, (3) disruption of repro¬
ductive processes, (4) visual impair¬
ment, especially nyctalopia, and (5)
loss of epithelial integrity.1 All of
these have been the subject of nu¬
merous inquiries, but except for the
visual cycle, the results constitute a
bewildering and complex set of iso¬
lated observations replete with con¬
tradictions. More recently, attempts
have been made to uncover some
basic molecular event from which

LUMEN
BLOOD
Fig 2.-Absorption and storage of vitamin
extrapolations can be made to clarify
the observed clinical phenomena.
Some interesting effects, still of un¬
known significance, have been found.
The role of vitamin A, primarily
vitamin A aldehyde, in the synthesis
of rhodopsin and in the photochemis¬
try of vision has been thoroughly
studied.' This constitutes the most
elegant demonstration of the physio¬
logic role of any vitamin. However,
the mechanism of action here does
not seem to afford an explanation of
other effects. Another sphere of
influence may be the ability of vita¬
min A to encourage or maintain
biosynthesis of mucopolysaccharides
through an enzymatic effect which
involves activation and transfer of
sulfate, but there is conflicting evi¬
dence in this regard.3,5" Even if the
effect is substantiated, it remains
problematic whether the effect is
primary or secondary to a more basic
effect on cell differentiation. One
mechanism whereby this more basic
effect might be executed was recently
proposed by De Luca and Wolf.lr>
They observed a decreased protein
synthetic capacity of ribosomes of the
rough endoplasmic reticulum in vita¬
min A deficiency. Subsequent studies
showed that this is due to inhibition
of amino-acyl transfer RNA synthe-
tase, the enzyme responsible for link¬
age of specific amino acid residues to
A.
transfer RNA prior to their incorpo¬
ration into the protein chain as di¬
rected by messenger RNA in the ri-
bosomes. This direction of protein
synthesis, if shown to be specific for
certain amino-acid-RNA complexes,
may be of basic importance in the
ability of vitamin A to control cellu¬
lar end products, specifically, keratin
vs mucin.
Another proposed role of vitamin
A has been that of an enzyme cofac-
tor. There are several enzymes re¬
ported to be decreased in activity in
vitamin A deficiency, including some
involved in mucopolysaccharide syn¬
thesis8 and steroid biosynthesis.16
However, under critical réévalua¬
tion, at least some of these enzymatic
effects may be secondary to inanition
rather than specifically due to lack of
vitamin A.17 Further well-controlled
studies are needed to resolve this
issue.
Finally, the most heralded action
of vitamin A is its ability to interact
with biologic membranes. There is
ample evidence of such an interac¬
tion, ranging from the induction of
hemolysis in erythrocytes of the
rabbit18 and mitochondrial swelling
in liver cells of the rat,lu to its potent
activity as a lysosomal labilizer.20,2'
Elaborate physicochemical models
have been proposed to explain this
interaction.2223 Some preliminary
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evidence exists that vitamin A may
be a normal constituent of plasma
membranes.23 In spite of the abun¬
dant evidence confirming the abil¬
ity of vitamin A to effect liberation of
lysosomal enzymes in vitro and in
vivo, the physiologic importance of
this function remains speculative.
However, vitamin A may be a regu¬
lator of membrane integrity, and this
may also explain some of its pharma¬
cologie attributes.
Epithelial Effects
Unfortunately, none of these mo¬
lecular events, or even all of them in
concert, is capable of readily explain¬
ing the observed epithelial effects of
the vitamin. This lack of correlation
results not only from a poor under¬
standing of the mechanism of action
but also from a surprisingly incom¬
plete knowledge of the nature of the
epithelial response. Before attempt¬
ing any explanation, therefore, it is
first necessary to examine the data,
such as they are, on this epithelial
interaction.
Since it was first proposed by
Harris et al in 1932,24 the term "anti-
keratinizing effect" has been widely
used as a succinct, albeit simplistic,
expression of the effect of vitamin A
on various epithelia. Although objec¬
tions to this term have recently been
voiced,25'211 it does seem a useful
starting point in explaining the
epithelial results of vitamin A
deficiency. If an antikeratinizing
effect is assumed, then deficiency of
the vitamin should favor keratiniza-
tion. This is precisely what is ob¬
served. For instance, in the skin the
clinical features of dryness, scaling,
and follicular papules (phrynoderma)
reflect a histologie state that is char¬
acterized by generalized hyperkera-
tosis with prominent follicular kera¬
tin plugs.27 More dramatic changes
occur in the sweat glands which, in
advanced disease, undergo atrophy
and keratinizing squamous metapla¬
sia.27,28 Comparable changes occur in
the mucous membranes of the nares,
trachea, bronchi, salivary glands,
and genitourinary tract, all of which
may become anatomically and func¬
tionally distorted by the production
of keratin.21' In the intestinal muco-
sa, there is atrophy and goblet-cell
degeneration but no keratin forma¬
tion.2" This implies that the different
epithelia have different thresholds of
responsiveness, as suggested by Fell
and Mellanby.3" Thus, the skin may
be regarded as having a high thresh¬
old which, even at normal plasma
levels of vitamin A, is able to resist
the antikeratinizing influence. The
gastrointestinal tract, however,
seems to have a low threshold, allow¬
ing expression of the antikeratinizing
effect even at very low plasma levels.
Further support for the antikera¬
tinizing effect was presented in 1953
when Fell and Mellanby3" demon¬
strated mucous metaplasia of nor¬
mally keratinizing epithelium under
the influence of excess vitamin A.
This finding received support one
year later when Kahn31 demonstrat¬
ed that vitamin A was able to locally
antagonize estrogen-induced corni-
fication of the vagina of the rat.
The antikeratinizing concept was
now firmly entrenched. It was easy
to visualize a reciprocal relationship
between keratin and mucin, with
vitamin A somehow directing cell
differentiation toward mucin secre¬
tion, with reversion to production of
keratin in its absence.
However, as more studies began to
accumulate, a much more complicat¬
ed picture evolved. It became evident
that Fell and Mellanby's original
observation in embryonic chick epi¬
dermis in organ culture,3" although
adequately confirmed ,l!'32,33 repre¬
sented a very special circumstance.
Further work demonstrated that the
effect of excess vitamin A was depen¬
dent on a number of variables that
included not only such obvious ones
as the chemical form of vitamin A
used, its concentration, and the dura¬
tion of exposure, but also such fac¬
tors as topical vs systemic adminis¬
tration, in vivo vs in vitro tech¬
niques, species differences, regional
differences in the same species, and
embryonic vs mature tissue. No sin¬
gle study or series of studies exists
which controls all of these variables;
therefore, in summarizing the re¬
sults of numerous investigations it
will be necessary to ignore vast
differences in technique, and this
Downloaded from www.archdermatol.com on November 12, 2010
Epidermal Effects of Excess Vitamin A
Embryonic
Effect Chicken
Keratinization Inhibited
Mucous metaplasia Present
Epidermal thickness
Mitotic index Increased
Parakeratosis
Granular cell layer
*
Except rat buccal mucosa.
t Except hamster cheek pouch.
should be borne in mind in evaluat¬
ing the conclusions.
In general, rodent epidermis,
whether fetal or adult, shows no evi¬
dence of mucous metaplasia when
exposed to excess vitamin A (Table).
30,34-43 There are
exceptions to this
generalization, however. Mucous
metaplasia has been observed in cer¬
tain mammalian epithelia, such as
the buccal mucosa of the rat,3r> the
esophagus of the embryonic rat,42
and the cheek pouch of the ham¬
ster.41 It is interesting, though, that
all of these exceptions involve epi¬
thelia with mucoid potential." Other
exceptions include the observation of
glandular metaplasia of vibrissae of
embryonic mice in organ culture,4"'
biochemical evidence of accelerated
mucopolysaccharide synthesis in the
absence of histologie changes,37 and
histochemical evidence of mucous
secretion (short of mucous metapla¬
sia) in skin of the embryonic
mouse.311,43 This latter point serves to
emphasize that, in general, embryon¬
ic skin is more responsive to vitamin
A than is mature skin, but that ro¬
dent embryos are still less responsive
than chick embyros. Finally, a vis¬
cid, mucinous secretion has been
observed to occur in rabbits with
experimentally induced keratoacan-
thomas who receive treatment with
topically applied tretinoin (trans-re-
tinoic acid).4"
As a further generalization, it may
be said that rodent epidermis not
only fails to exhibit mucous metapla¬
sia but also shows little evidence of
keratinization inhibition.311,34 43 Here
again, those epithelia with mucoid
Mature
Rodent Rodent
Minimal or Minimal or
no inhibition no inhibition
Absent* Absentt
Increased Increased
Increased Increased
(low dose)
Decreased
(high dose)
Present Present
Increased
potential must be excepted and cer¬
tain qualifications should be placed
on what is meant by inhibition of
keratinization. Most authors have
observed the development of para-
keratosis and increased prominence of
the stratum granulosum, both of
which may be logically considered
interference with keratinocyte ma¬
turation or "keratinization inhibi¬
tion."47 It would seem more appropri¬
ate to use the term "disturbance" or
"abnormality" of keratinization for
this phenomenon, rather than inhibi¬
tion of keratinization, which implies
an actual decrease in the production
of keratin and keratin precursors.
Rodent epidermis continues to pro¬
duce adequate, even abundant,
amounts of keratin under the
influence of vitamin A, but changes
observed in the stratum corneum
and stratum granulosum do imply a
departure from the normal, orderly
sequence of keratin formation. How¬
ever, there is again some evidence of
heightened reactivity of embryonic
skin in which true inhibition of kera¬
tin formation has been reported.43
A major effect of excess vita¬
min A on rodent epidermis involves
histologie findings consisting of
hyperplasia (acanthosis), parakerato-
sis, and an increased mitotic in¬
dex 34,38,88,«,48,49 Taken in concert,
these changes are suggestive of ac¬
celerated epidermal dynamics and a
rapid turnover time. However, taken
by themselves, the histologie effects
justify this conclusion only by analo¬
gy to the well-studied dynamics of
psoriasis. None of these findings nec¬
essarily implies increased cellular
turnover. Even the striking increase
in mitoticfigures could be explained
by prolongation of the mitotic event,
allowing more divisions to be seen at
any given moment, but not resulting
in more rapid turnover. Recently,
however, a threefold to fourfold in¬
crease in epidermal transit time in
guinea pig skin under the influence
of tretinoin has been documented.47
Fulton et al5" also claim to have
confirmed the accelerated turnover
but have not provided any data.
In spite of these results/ it is not
acceptable to state without reserva¬
tion that vitamin A induces epider¬
mal hypertrophy and an increased
mitotic index. Such a statement
must be qualified by dosage consider¬
ations, since Sherman4" and Law¬
rence et al41 have shown that high
doses of vitamin A, which may im¬
pair keratin production and result in
mucous metaplasia, fail to induce
acanthosis and actually diminish
mitotic activity. Thus, there appears
to be a dual effect, with interference
with keratin formation predominat¬
ing at higher doses and cellular pro¬
liferation occurring at lower doses.
The observed accentuation or
induction4" of the stratum granulos¬
um requires additional comment.
Lever51 stated that the thickness of
the stratum granulosum correlates
inversely with the rapidity of kera-
tinocyte turnover. This would imply
that the prominent granular cell
layer seen after vitamin A exposure
reflects adecrease in cellular turn¬
over, an implication obviously in
conflict with the preceding discus¬
sion. The conflict is resolved, how¬
ever, by reference to recent autoradio-
graphie studies52 which established
a greatly accelerated turnover time
for lamellar ichthyosis and epider-
molytic hyperkeratosis, both of
which may be associated with a con¬
spicuously increased granular cell
layer. Thus, no simple relationship
exists between the prominence of the
granular cell layer and epidermal
turnover, and the inverse correlation
previously mentioned must be re¬
garded as no longer tenable. This
suggests that the pronounced stra¬
tum granulosum occurring after vi¬
tamin A exposure may simply repre-
Downloaded from www.archdermatol.com on November 12, 2010
sent a nonspecific hypertrophy such
as occurs in the malpighian layer.
However, the possibility of a direct,
and possibly important, effect on the
poorly understood formation of kera-
tohyalin seems likely.
Finally, it must be questioned
whether the observed hyperplasia
and increased mitotic figures are
specific for vitamin A. The same his¬
tologie changes have occurred after
the topical application of several
compounds, particularly olive oil,
xylene, and oleic acid,3"41,53 and have
been regarded as a nonspecific re¬
sponse to epidermal injury.40 A major
difference does exist, however, in
that the response of the epidermis to
"irritants," such as those previously
mentioned, also includes evidence of
cell damage and death, which does
not occur after vitamin A expo¬
sure.39,40 This has led to the conclu¬
sion that the observed epidermal
effect of vitamin A reflects a specific
pharmacologie attribute of the vita¬
min.40 Montagna39 also noted this
difference in histologie effect but at¬
tached no significance to it, and re¬
garded the effect of vitamin A as
nonspecific.
All of the previous data have been
derived from experimental animal
studies. In view of known species
differences, these data should not be
casually applied to humans. Al¬
though numerous reports have indi¬
cated histologie changes in patho¬
logic situations before and after
treatment with vitamin A, relatively
few studies have reported the effect
of vitamin A on normal human
skin.54 58 Generally, the findings have
been similar to those noted on rodent
skin. Most authors have cited epider¬
mal thickening, parakeratosis, and
prominence of the granular cell layer
as being conspicuous,54,55,58 but Fish¬
er and Herrmann57 did not detect
any epidermal thickening, using
planimetric methods. There is very
little information with regard to
changes in the mitotic index. Pinkus
and Hunter54 reported a decreased
number of mitotic figures and a slug¬
gish response to cellophane-tape
stripping after one month of treat¬
ment with orally administered vita¬
min A —a circumstance unlikely to
result in very high cutaneous con¬
centrations.25 Kligman et al,59 how¬
ever, in their study of patients with
acne, documented increased uptake
of tritiated thymidine after treat¬
ment with topically applied tretinoin,
lending support to the occurrence of
a proliferative response in humans.
As in rodents, the only study of
human embryonic skin5'1 suggests a
heightened reactivity, as evidenced
by complete suppression of keratin
formation and the appearance of
PAS-positive intracellular granules;
no true mucous metaplasia occurred.
Finally, Kligman et al5" called at¬
tention to lessened cohesiveness of
horny squames after exposure to top¬
ically applied tretinoin. Although
this finding had not been emphasized
in previous studies, there are several
notes of its occurrence,'"'55 including
electron microscopic evidence of
the widening of intercellular lacu-
nae :¡h,«),«i Also, Weiss112 has indepen¬
dently postulated that vitamin A de¬
creases cellular cohesiveness on the
basis of facilitated detachment of
vitamin A-treated cells from various
artificial surfaces by a standard
shearing force.
The following conclusions regard¬
ing the epithelial effects of vitamin A
are justified.
1. Excess vitamin A, in low or
moderate doses, results in an in¬
creased mitotic index, hyperplasia
(acanthosis), parakeratosis, and a
rapid turnover time. This effect may
be reversed by higher doses. There is
also an associated prominence of the
granular cell layer of uncertain
cause.
2. There is moderate interference
with keratinocyte maturation which
seems to be more than simply sec¬
ondary to the rapid turnover and
which is the predominant effect at
higher doses.
3. In embryonic chicken skin and
in mammalian epithelia with mucoid
potential, keratinization may be
completely suppressed, with re¬
sultant mucous metaplasia. This
effect may be partially expressed in
mammalian embryonic skin.
4. Diminished cellular cohesive¬
ness is postulated.
5. The term "antikeratinizing
effect," although possibly not incor¬
rect, is incomplete and appears to be
no longer useful.
Mechanism of Action
Precisely how vitamin A is able to
elicit its varied effects is unknown.
Flesch'13 has suggested that the con¬
jugated double bonds are responsible
for the "antikeratinizing effect," pre¬
sumably as a result of binding with
sulfhydryl groups, because of a loss
of epilating ability in rabbits after
saturation of the double bonds. This
does not consider the fact that any
alteration of the vitamin A molecule,
regardless of how minor, results in a
loss of biologic activity.3 Thus, re¬
moval of a methyl group may have
given the same results, but with
different conclusions. The influence
of vitamin A on mucopolysaccharide
synthesis may have a role in the
appearance of mucous metaplasia,
but this effect is currently controver¬
sial and appears to have no rele¬
vance to the predominantly prolifera-
tive effect in mature, mammalian
epidermis.
The demonstration of a mechanism
for theoretic control of the final prod¬
uct of the cell by selectively in¬
hibiting amino-acyl transfer RNA
synthetases15 is a relatively new dis¬
covery so far unheralded in the liter¬
ature. Such an effect provides an
explanation for control over cyto-
differentiation but, again, does
not readily account for the mitogenic
effect. Nevertheless, this seems to be
a promising approach, if confirmed.
1. Marks J: The Vitamins in Health and Dis-
ease: A Modern Reappraisal. Boston, Little
Brown & Company, 1968, pp 42-54.
2. Roels OA: Vitamin A physiology. JAMA
214:1097-1102, 1970.
3. Olson JA: Recent developments in the fat\x=req-\
soluble vitamins: Metabolism and function of
vitamin A. Fed Proc 28:1670-1677, 1969.
4. Wald G: Molecular basis of visual excita-
tion. Science 162:230-239, 1968.
5. Pelc SR, Fell HB: The effect of excess vita-
min A on the uptake of labelled compounds by
embryonic skin in organ culture. Exp Cell Res
19:99-113, 1960.
6. Rothberg S: The cultivation of embryonic
chicken skin in a chemically defined medium,
Downloaded from www.archdermatol.com on November 12, 2010
The most commonly accepted
mechanism, the one with the most
experimental evidence and the one
that explains more of the observed
effects, is vitamin A's potent labiliza-
tion of lysosomal membranes. This
provides a ready explanation of the
decreased cohesiveness of the keratin
by acceptance of the intercellular
space as the ultimate depository for
some of the released hydrolytic en¬
zymes.114 It is reasonable that exces¬
sive amounts of these enzymes could
destroy much of the intercellular
cement, resulting in the widened
intercellular lacunae seen electron
microscopically and the histologie
evidence of loosely packed keratin.
Also, there is some tissue culture
evidence that the release of lysosomal
enzymes can, under certain circum¬
stances, stimulate mitotic activity,115
and there is no reason why this
might not occur in vivo. The in¬
creased prominence of the stratum
granulosum is not easily attributed
to lysosomal labilization, however.
The fact that during orthokeratini-
zation the release of lysosomal en¬
zymes is most conspicuous at the
granular cell level does not consti¬
tute valid evidence that the appear¬
ance of keratohyalin granules is a
consequence of the enzymatic activ-
ity.
Therapy
The recent reports'111'117 of successful
treatment of psoriasis and certain
ichthyoses with topically applied
tretinoin give rise to a perplexing
References
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7. Pasternak CA, Thomas DB: Metabolism of
sulfated mucopolysaccharides in vitamin A
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8. Wolf G, Varandani PT: Studies on the
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9. Varandani PT, Wolf G, Johnson BC: Func-
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response of the skin to vitamin A,
why should vitamin A acid benefit
diseases that are characterized by
accelerated turnover times?52,08 And
what relationship does this have to
the reported control of Darier's
disease5" in which the basic defect
appears to be a genetically deter¬
mined faulty keratinization? Finally,
why is vitamin A acid, as opposed to
the alcohol, aldehyde, and palmitate,
so uniquely potent in this regard?011
It is this emerging therapeutic po¬
tential and the intriguing questions
it has raised which have prompted
this review. Unfortunately, experi¬
mental data on the effects of treti¬
noin on keratinization and epidermal
kinetics are just beginning to accu¬
mulate. The vast majority of data
presented above has accrued from
work with vitamin A and vitamin A
esters. It remains to be established
whether vitamin A acid, when ap¬
plied to normal human skin in the
clinically useful concentrations of
0.05% to 0.3%, has the same or
different effects. With such limited
knowledge, it is apparent that specu¬
lations with regard to the mecha¬
nisms of action of tretinoin are gross¬
ly premature at this juncture and
must await the results of specifically
designed experimental studies.
Nonproprietary and
Trade Names of Drug
Tretinoin Retin-A.
—
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17. Rogers WE Jr: Reexamination of enzyme
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zyme role for vitamin A. Amer J Clin Nutr 22:
1003-1013, 1969.
18. Dingle JT, Lucy JA: Studies on the mode
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tamin A on the stability of the erythrocyte mem-
brane. Biochem J 84:611-621, 1962.
19. Lucy JA, Luscombe M, Dingle JT:
Studies on the mode of action of excess vitamin
A: VIII. Mitochondrial swelling. Biochem J 89:
419-425, 1963.
20. De Duve C, Wattiaux R, Wibo M: Effects
of fat-soluble compounds on lysosomes in vitro.
Biochem Pharmacol 9:97-116, 1962.
21. Dingle JT: Studies on the mode of action
of excess of vitamin A: III. Release of a bound
protease by the action of vitamin A. Biochem J
79:509-512, 1961.
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