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FISHERIES AND MARINE SERVICE
Translation Series No. 4454
The specificity of cholesterol absorption and its
biological significance
by R. Schoenheimer,
Original title: Die Spezifitat der Cholesterinresorption und Ihre
Biologische Bedeutung
From: Klin. Wochenschr. 11: 1793-1796, 1932
•
Translated by the Translation Bureau (MMA)
Multilingual Services Division
Department of the Secretary of State of Canada
Department of the Environment
Fisheries and Marine Service
Halifax Laboratory
Halifax, N. S.
1978
10
pages typescript
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1.
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zilleLI
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AUTHOR — AUTEUR
Schoenheimer, R.
TITLE IN ENGLISH — TITRE ANGLAIS
The specificity of cholesterol absorption and its biological
significance
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TITRE EN LANGUE ÉTRANGÈRE (TRANSCRIRE EN CARACTÈRES ROMAINS)
Die Spezifitàt der Cholesterinresorption und ihre biologische
Bedeutung
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Klinische Wochenschrift
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Clinical Weekly
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Die Spezifitàt der Cholest#rinresorption und
ihre biologische Bedeutung .
[The specificity of cholesterol absorption and its
biological significance]
Klinische Wochenschrift 11: #43, 1793-1796 (1932)
Lecture delivered at the Meeting of the 'Deutsche Naturforscher
und Xrzte' [German Natural Scientists and Physicians] on
September 28, 1932. The work was done in part with funds
provided by the Josiah Macy jr. Foundation.
UNEDUED
For informa:ion
TRADUCTUDN NON REVISEE
Information seulement.
SEC 5-25 (Rev. 6/78)
2
Cholesterol belongs to a group of biologically important
substances which - with suitable input - are easily absorbed. There
is a vast array of experimental arrangements by which this can be
proven in acute or chronic tests. A somewhat crude method which
is, however, of general biological and pathological interest, is
the method of feeding rabbits or other animals cholesterol over
an extended period of time during which the absorbed material is
deposited in various tissues; in the most sensitive tissue, that
of the intima of the aorta this may lead to very enormous deposits
greatly resembling those seen in human atherosclerosis. Therefore,
it can be regarded as an experimental atherosclerosis model (1).
Even extremely small amounts of cholesterol or of animal organs
containing cholesterol given over a longer period of time suffice
to produce such typical changes in rabbits, changes which normally
are never observed in this species. It is true that spontaneous
aorta calcifications are frequently found in rabbits. But, so
far, despite the most thorough investigations / spontaneous fatty
cholesterol ester degeneration, such as that characteristic for
"feeding atherosclerosis," has never been described by any author.
For this reason the rabbit is particularly suitable for experiments
on cholesterol metabolism.
The rabbit is a purely herbivorous animal and thus
not accustomed to any supply of cholesterol in the food. Cholesterol
does not occur in plants; it is limited exclusively to higher
animals. On the other hand, substances which are chemically and
physically extremely closely related to cholesterol are found in
all plants. They are called plant sterols or phytosterols. Whereas
it is primarily cholesterol that is encountered in the animal organism, plant sterols are usually present in very complex mixtures;
as separation of substances which are chemically so very similar
is extraordinarily difficult, it may be assumed that currently
only very few of the actually existing plant sterols are known.
The most widespread and best kno\;en of these is the so-called sitosterol which of all the plant sterols is the one that most closely
*According to L8WENTHAL spontaneous intima fatty degeneration
does sometimes occur in mice.
resembles cholesterol (Windaus and Rahlen [2 1 ) .
The extremely complicated chemical structure of the
sterols and the fact that the animal constantly takes up such
substances with its vegetable food, has led to the assumption
that - following absorption - the animal converts these sterols
to cholesterol by simple chemical reactions. But, if this original
1794
assumption were correct, spontaneous "feeding atherosclerosis"
should be in evidence in every rabbit because the quantity of
plant sterols taken up daily with the food should lead to severe
changes after their conversion to cholesterol.
This difference between assumption and actual evidence
has prompted the following experiments on sterol absorption:
Feeding very large quantities of isolated plant sterols,
primarily sitosterol, never led to sterol deposits in rabbits
or other animals (3, 4).The cholesterol content of the blood,
which assumes very high values in the course of cholesterol feeding,
remained normal throughout the entire experimental period: there
was no evidence of elevated cholesterol levels in animals which
were analyzed in their entirety after they had been killed, nor
were traces of plant sterols detected along with the cholesterol
(5). Later, in balance experiments, it was established that
when pure plant sterols are fed, a quantity of sterols commensurate
with the amount fed is eliminated with the feces, and that in
its chemical properties the sterol eliminated is identical with
the sterol fed (6, 7, 8).
Experiments in which a thoracic duct fistula was used seem
to give the most unequivocal results. The absorbed cholesterol
migrates from the intestine into the body primarily through the
lymph and there - in a manner of speaking, on the other side of
the intestinal wall - it can easily be recovered. When cholesterol
was fed together with plant sterols, only pure cholesterol could
* According to more recent investigations even sitosterol is
still a mixture of three different optical isomers (Anderson,
J. of biol. Chem. 48: 2987 (1926) - BONSTEDT, Hoppe-Seylers Z.
140: 269 [19231).
4
be isolated from the duct lymph; not a trace of plant sterols
was found (9)
These experiments show unequivocally that despite the
great similarity with the readily absorbable cholesterol, the
plant sterols are not absorbed and are treated as 'foreign'
substances by the intestinal tract, i.e. substances which the
organism redects.
All these experiments were encumbered by some small error
due to the biological method used and to chemical analysis. The
best analytical method for sterol assays, the method of Windaus,
still has a margin of error of about 2%. Thus, nothing can be
said on quantities below this limit. Therefore, the possibility
that very small amounts which would escape detection by this
method might nevertheless be absorbed and deposited, cannot be
precluded.
Originally an argument favoring this assumption was the
fact that minute quantities of ergosterol were present in the
body, amounts which were thought to hall from the plant, to be
deposited in the tissue after absorption, and then converted
to the highly active vitamin D after the skin has been irradiated
with ultraviolet light.
When ergosterol is included in absorption experiments
a strict distinction must be made between non-irradiated, inactive
ergosterol on the one hand, and the irradiated, active form on
the other. Chemically they are isomeric substances; they differ
not only in their biological but also in their physical and
chemical properties. It is, of course, beyond doubt that the
irradiated form (vitamin D) is readily absorbed; otherwise it
would not display any biological activity after it is fed, and
in the case of overdosage it may even be highly toxic. The results elicited by analyzing the non-irradiated form of ergosterol,
i.e. the biologically inactive substance, were different from what
had been anticipated. Absorption experiments with this product
were much more accurate and sensitive than experiments with other
sterols, inasmuch as - with the aid of absorption in ultraviolet
light and testing on the biological object - the analysis of
ergosterol is approximately one thousand times more sensitive than
5
analysis of any other plant sterol. Even the most minute amounts
of absorbed ergosterol can hardly escape detectiore. Despite
an enormous supply with the food, like the other sterols, ergosterol could not be stored (12, 13).
But, as storage experiments with negative results can never be regarded as definitive
proof that no absorption takes place, because there are quite
a number of other possible explanations, direct absorption experiments were carried out on dogs with thoracic duct fistulas:
the results revealed that when large quantities of a mixture of
50% of cholesterol and 50% of ergosterol were fed, only pure
cholesterol was recovered, with a maximal ergosterol content of
0.02 to 0.03% (11), which corresponds to the normal ergosterol
content in thoracic duct sterols. If cholesterol and ergosterol
had been absorbed at an equally rapid rate, about 2000 to 3000
times more ergosterol would have had to be recovered in the
lymph. However, at this time even these experiments do not
entirely preclude the possibility that minute quantities of this
substance, still beyond the limit of sensitivity of the optical
method, may be absorbed and - upon constant supply - might
display some biological activity in view of the fact that after
irradiation this substance is highly active. What is certain,
however, on the basis of all the above experiments,is that if
absorption takes place at all, it can only be of an extremely
low order of magnitude ** .
These unique biological differences between such similar
sterols suggest that a peculiar, uncommon specificity prevails
in this class of compounds with respect to absorption, a specificity which is probably also of particular biological significance. Therefore, experiments with chemical derivatives of
cholesterol were carried out: only very minor changes were
made in the molecule, the special peculiarities of the sterol
compound were preserved (4).
*The ergosterol analyses of our preparations were kindly performed by the Chemical Institute of the University of Gdttingen
for which I wish to express my most sincere gratitude to
Professor Mndaus, Dr. Pallutz and Dr. v. Gottberg.
** Recently minimal ergosterol absorption has been demonstrated
in the laying hen (SCHdNHEIMER and DAM, in press).
6
CH,
CH, .
/t
H2C 3 t ICH—i
I
I
I
"2
C
'
\9/
C—CH,
I
!I
!C141122
HCt toCH- 1
H2 C2
/\
CH-H2C
r
scH 7 cH
/Nje
C C
/\
/\/
H OH
H OH
Allocholesterin
Cholesterin
CH,
/\
CH-1
1C14H28
I
CH—) -
I
HC
/ \ /
H2C C—CH,
3
I
I
CH CH 2
I
H2C
CH2
/\
112C CH-
C14H23
I
I
CH CH—)
/ \ /
H2C C—CH,
I
I
CH,
C
/\
.
Koprosterin
Dihydrocholesterin
CE,
I
CH2
/\
CHH2C
}C14H 28
CH—
HC
/\ /
H2C C— CH
I
H 2C
I
I
CH CH,
C CH,
/\
OH
H
e - Cholestanol
4
H OH
H OH
I
I
CH CH 2
H2C
\/\/
C CH 2
/\
\/\/
/\
H 2C
CH—
2
I
CH CH,
1
112C
\/\/
C CH,
C3
H2C
}C,41-1„5
-
H2C C—CH 2
I
81
CH—
5
:
IC141-1 22
I
I
CH CH-
/ \ / H2C C—CH2
I
6
I
I
CH CH,
H,C
\/\/
C CH,
OH H
Pseudokoprosterin
1795
The major interest focussed on investigation of
the allocholesterol because it resembles cholesterol most
closely and only differs from it by a shift in the double bond.
A new quantitative method of determination was used: it was
impossible to detect any absorption of the allocholesterol.
Although a sterol is absorbed following feeding of this substance,
this sterol is cholesterol which has evolved from the highly
sensitive allocholesterol by action of the acid gastric juice * .
* SCHhHEIMER, DAM and v. GOTTBERG, currently in press.
7
Nor was even a single one of the other substances in the Table
absorbed. Very sensitive methods for the detection and determination
of these substances were elaborated and it would have been impossible to overlook them. This striking result gains special
importance by the fact that dihydrocholesterol and coprosterol
(formulas 3 and 4) occur in the intestinal tract, i.e. these
are biological animal sterols. Thus, this investigation shows
that absorption of cholesterol is indeed highly specific: even
the most minute changes in the molecule which barely alter the
general behavior of the substances, can already abolish absorp*
tive capacity .
As far as I know, such specificity of absorption, dependent
on the constitution of certain substances, has never before been
observed in physiology. Usually the rate of penetration through
the intestinal wall depends solely on the solubility of the
particular compound, and changes in absorptive capacity only
parallel changes in the molecule to the extent that changes in
the chemical structure are accompanied by differences in solubility. But the sterols investigated are extraordinarily similar
in their chemical and physical behavior, and especially in their
solubility. In some cases one is only dealing with isomers with
very minor changes in their chemical properties. These differences
could hardly explain the different behavior with respect to
absorption.
According to recent views, the absorption process of
**
water-insoluble compounds
rests on a purely physical process
(Verzr [14]), i.e , such substances are converted to soluble,
diffusible addition compounds by other so-called hydrotropic compounds (Neuberg). It is now almost beyond doubt that the presence
of bile acids, which can enter into such addition reactions, is
favorable for the absorption of lipids as well as sterols, and
may bven be necessary. Sterols do indeed form such soluble aggre*Recently the fact that dihydrocholepterol and coprosterol cannot
be absorbed has been confirmed by BURGER and WINTERSEEL.
** All sterols investigated are insoluble in water.
8
gates with bile acids (although these are not diffusible in
their entirety)(15), and the types of these compounds formed
with the various sterols are almost identical. Although almost
all bile acids considerably accelerate the absorption of cholesterol (16, 17, 18), even with their assistance an otherwise nonabsorbable sterol cannot penetrate the intestinal wall, not even
when enormous quantities of that sterol are fed. While it is
possible that with respect to other insoluble substances the physical
solubility conditions may play a decisive role, in Verzàr's
sense of the term, this cannot be the case in the sterol group.
One is probably not amiss in assuming that the significant
factor in absorption specificity is that it affords the organism
an opportunity to protect itself against the entry of or flooding
with sterols foreign to its own species. Unfortunately, at
this date we know very little about this subject, for instance
whether these foreign sterols, e.g. plant sterols, have any
pharmacological or toxicological effect in the organism. Since
these compounds cannot be absorbed feeding experiments are ruled
out. Nor, with the methods available at this time, can injec. *
tion experiments provide any valid information . Thus, a decision will have to be left to the future. Today the significance
of impeding absorption can only be understood with respect to
one sterol, namely ergosterol. While the non-irradiated ergosterol (so-called provitamin D), present in large quantities in
plants (e.g. yeast) per se is physiologically inactive, after
irradiation it becomes enormously active (in the sense of vitamin
D) and - at larger doses - can then cause severe general distrubances including calcifications. If ergosterol were as readily
absorbable as cholesterol, under the appropriate nutritional
conditions, the organism might easily be flooded with ergosterol,
which - following activation by skin irradiation - might cause
*So far attempts to bring larger amounts of sterols into solution
in a manner in which they can be injected have failed. The
so-called colloidal cholesterol solutions frequently used display
an entirely unphysiological activity. Following injection, the
cholesterol is very rapidly recovered from the reticular endothelium and especially from the pulmonary capillaries. In the socalled colloidal distribution, which is apparently quite different
from that in the blood, cholesterol is treated like a foreign
compound (cf. LINENTHAL).
•
9
toxic manifestations. The fact that the non-irradiated
substance is either hard to absorb or cannot be absorbed at
all protects the organism against this eventuality.
Specificity of sterol absorption is also an important
factor in the excretion of these substances. The amounis
of sterols poured daily into the intestine are extraordinarily
large. The bile only carries with it a very small part of that.
The major portion is flushed out with the intestinal secretions
(Salomon [20], Sperry [21]). The sterol which is secreted originally consistsb about 97% of cholesterol and 3% of dihydrocholesterol; the latter is formed in the organism from cholesterol
by saturation of the double bond with hydrogen. Apparently in
part the secretion of these substances is a cellular process,
i.e. the sterols originate from cells which migrate into the
intestinal lumen (leukocytes and lymphocytes)(24) and rapidly
decay in the secretions. While the major portion of the sterol
liberated from the cell body, to wit the cholesterol, is absorbable,
the dihydrocholesterol accumulates in the intestine and appears
at relatively large concentrations in the secretions. This
process can be observed quite unequivocally in sterile intestinal
loops (cysts) of the colon (23) and small intestine (25) closed
at both ends: as time goes on more and more dihydrocholesterol
will accumulate there, whereas the cholesterol disappears. In
this manner dihydrocholesterol, which only occurs at very small
amounts in the organism and is apparently merely a waste product,
can be concentrated and leave the body with the feces.
In this context it should be pointed out that not all
the cholesterol secreted into the intestine is reabsorbed. Part
of it is attacked by intestinal bacteria before it can be reabsorbed
and converted to coprosterol (formula 4); it is then also
non-absorbable.
In some respects the intestine can apparently act in
a manner similar to the kidney which first secretes numerous
substances, but then reabsorbs most of these from the originally
secreted material (e.g. sugar, etc.) and finally only eliminates
the waste which cannot be reabsorbed, with the urine. Findings
elicited on sterile intestinal cysts, also with substances
other than sterols, will be further discussed elsewhere.
*******************
REFERENCES
Literatur: 1 ANiTscÉxow, Virchows Arch. 249, 73 (1924). —
Hoppe-Seylers Z. lox, 223 (1918). — 3 SCHÔNWEIMER U. YUASA, Eloppe-Seylers Z. /80, 5 (1929). — 4 SCHÔNHEIMER, V. BHERING U. HUMMEL, Hoppe-Seylers Z. 192, 117 (1930).
— 5 SCHÔNHEIMER, Hoppe-Seylers Z. 180, 16 (1929). — 6 SCHÔNREIMER, Hoppe-Seylers Z. Co, 32 (1929). — 7 SCHÔNHEIMER,.
HOppe-Seylen Z. 185, 119 (1929). —
DORRÉ U. GARDNER, Proc.
roy. Soc. Lond. 80, 217 (1908). —
V. BEHRING U. SCHÔNHEIMER,
Hoppe-Seylers Z. 192, 97 (1930). — 1 ° PAGE, Biochem. Z. 22b, 420
(1930). — 11 SCHÔNHEIMER U. V. BEHRING, Min. Wschr. 1930, 2308.
— 12 BEUMER U. HEPNER, BiOCIle111. Z. 222, 204 (1930). — 13 SCHÔN2 WINDAUS U. RALÉN,
--
HEIMER,
Hoppe-Seylers Z. 192, 77 (1930). — VERZAR U. KUTHY,
Bi0CheITI. Z. 205, 369 (1929); 210, 265 U. 281 (1929). —
SCHÔN-
Proc. Soc. exper. Biol. a. Med. 28. 944 ( 1 93 1 ). —
SCHôNHEIMER, Biochem. Z. 147, 258 (1924). — 17 LÔFFLER,
Hoppe-Seylers Z. 178, 186 (2928). — 18 HUMMEL, Hoppe-Seylers Z.
285, 105 (1929). — 19 SCHôNHEIMER U. YUASA, Hoppe-Seylers Z. 180,
19 (1929). — 2 ° H. SALOMON, Z. exper. Med. 6o, 750 (1928). —
21 SPERRY, J. physiol. Chem. 82, 56 0 (1929); 85, 455 (1930). —
22 SCHÔNHEIMER, V. BEHRING, HUMMEL U. SCHINDEL, Hoppe-Seylers
Z. 292, 73 (1930). — 23 OHNO, BlOCIleM. Z. 218, 206 (1930). —
24 SCHôNHEIMER. U. V. BEHRING, Hoppe-Seylers Z. 292, 102 (1930). —
25 1m Druck.
HEIMER U. HRDINA,
in press.