Mechanisms of thiamin deficiency in chronic

alcoholism1 -3

Anastacio M. Hoyumpa, Jr., M.D.

ABSTRACT In the United States and other developed countries thiamin deficiency is often
related to chronic alcoholism. A number of mechanisms may be involved in the pathogenesis of
thiamin deficiency in the alcoholic population. An important cause is inadequate intake of thiamin.
Moreover, there may be decreased converstion of thiamin to the active coenzyme, reduced hepatic
storage of the vitamin in patients with fatty metamorphosis, ethanol inhibition of intestinal thiamin
transport, and impaired thiamin absorption secondary to other states of nutritional deficiency. The
present discussion focuses on the mechanism of ethanol-related thiamin malabsorption. Under
normal conditions thiamin transport in animals and humans is biphasic. At low or physiological
thiamin concentrations, transport is a saturable, carrier-mediated, active process; but at higher
concentrations, the transport of thiamin is predominantly passive. Ethanol reduces the rate of
intestinal absorption and the net transmural flux of thiamin. Furthermore, ethanol inhibits only
the active and not the passive component of thiamin transport by impeding the cellular exit of
thiamin across the basolateral or serosal membrane. The impairment of thiamin movement out of
the enterocyte correlates with a fall in the activity of Na-K ATPase. Bound to the basolateral
membrane, Na-K ATPase is believed to be involved in the kinetics of active transport. Ethanol
also increases the fluidity of enterocyte brush border and basolateral membranes. Since ethanol
increases membrane fluidity it is possible that the impairment of thiamin transport and the
diminution of Na-K ATPase activity may be related, at least partly, to a physical perturbation of
the enterocyte membrane. Am. J. Clin. Nutr. 33: 2750-2761, 1980.

Thiamin was the first member of the vi- include insufficient intake of the vitamin,
tamin B complex to be chemically identified. decreased formation of thiamine pyrophos-
In the presence of ATP it is converted to phate, reduced hepatic thiamin storage, in-
thiamin pyrophosphate which functions in hibition of intestinal thiamin transport by
carbohydrate metabolism as a cocnzyme in ethanol, and secondary impairment of thia-
the decarboxylation of pyruvic and a-keto- mm absorption due to ethanol-related nutri-
glutaric acids and in the utilization of pcntose tional deficiencies. Each of these factors will
in the hexose monophosphate shunt. A seri- be discussed separately, but emphasis will be
ous deficiency of thiamin leads to accumula- placed on the effect of ethanol on intestinal
tion of pyruvate and a-kctoglutarate in the transport of thiamin as this has been the
blood and a decrease in the activity of trans- subject of active investigation.
ketolasc. Clinically, lack of thiamin is char-
acterized by neurological and cardiovascular Insufficient thiamin intake
disturbances that give risc to Wernicke-Kor-
sakoff syndrome, peripheral neuritis, and The requirement of thiamin depends upon
beri-beri heart disease. the metabolic rate. In man the minimum
In underdeveloped countries thiamin defi- requirement is 0.33 mg/l000 cal but to pro-
cicncy is generally the result of poor dietary
practices such as eating mainly polished rice From
I the Veterans Administration Medical Center
and other food preparations containing anti- and Vanderbilt University School of Medicine, Nash-
thiamin factors, but in the United States and vile, TN.
2Supported by the Medical Research Service of the
other developed countries thiamin deficiency
Veterans Administration.
is often related to chronic alcoholism (1-4). 3Address reprint requests to: Anastacio M. Hoyumpa,
The circumstances which may be responsible Jr., M.D., VA Medical Center, Nashville, Tennessee
for this association are listed in Table 1 and 37203.

2750 The American JournalofClinical Nutrition 33: DECEMBER1980, pp. 2750-2761. Printed in U.S.A.

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 THIAMIN DEFICIENCY IN CHRONIC ALCOHOLISM 2751

TABLE 1 was measured in rats fed ethanol chronically

Possible mechanisms of thiamin deficiency in chronic
there was a suggestive decrease (13) which,
alcoholism
however, did not reach statistical significance
1. Inadequate thiamin intake possibly because of the small number of de-
2. Decreased activation ofthiamin to thiamin pyrophos- terminations. Despite these suggestive find-
phate
ings the abnormal conversion of thiamin to
3. Reduced hepatic storage of thiamin
4. Inhibition of intestinal thiamin transport
the active coenzyme remains to be proved.
5. Impairment of thiamin absorption due to ethanol- Studies must be designed to rule out impaired
related nutritional deficiency states intestinal absorption of thiamin as a major
factor contributing to the lowered concentra-
tions of hepatic thiamin or decreased activity
vide a margin of safety a daily consumption of thiamin-dependent enzymes.
of 0.5 mg/l000 cal is recommended by the
Food and Nutrition Board of the National
Research Council. The actual daily consump- Reduced hepatic storage
tion of thiamin by healthy subjects usually
The liver is a principal storage depot for
ranges from 0.4 to 2.0 mg (5). In contrast,
thiamin, and normally contains 2.0 to 7.6
alcoholic subjects tend to consume less than
mg/g moist tissue (14) compared to 1.4 to 4.1
0.29 mg/l000 kcal of thiamin (2). This find-
in the brain and 2.8 to 7.9 in the heart. In
ing is consistent with the observation that of
patients with severe alcoholic liver disease,
3000 alcoholic patients, admitted to a large the thiamin content may be reduced by as
municipal hospital because of withdrawal much as 73% (1, 15). Inhibition of thiamin
symptoms or intercurrent illness, evidence of uptake into isolated rat hepatocytes by
dietary deficiency occurred during periodic ethanol was demonstrated in one study (16),
binges of alcoholic drinking in 40%. Pro- but not in another (17). Moreover, in liver
longed dietary deficiency alternating with a perfusion studies, ethanol was shown to cause
marginal or normal diet during periods of the release of thiamin from the liver (18).
abstinence was observed in 25%, and contin- These factors, along with the decrease in
uous dietary deficiency was a feature in an- functioning hepatic parenchyma in the pres-
other 35% (6). In such patients the presence ence ofsevere fatty metamorphosis, may con-
of anorexia and intake of inadequate and tribute to decreased storage of thiamin.
unbalanced diet during alcohol consumption
(which provide only “empty calories”) con-
tribute to the dietary deficiency. Ethanol inhibition of thiamin absorption

Characteristics of normal thiamin transport

Decreased formation of thiamin
pyrophosphate Many studies of intestinal thiamine trans-
port have been carried out in the past utilizing
The conversion of thiamin to thiamin py- different methods and various animal species,
rophosphate may be impaired in the presence often with conflicting results. From an exten-
of alcoholic liver injury, possibly because of sive review of the literature Rindi and Ven-
decreased availability or use of ATP (6) and tura (19) concluded that the intestinal trans-
may be associated with decreased activity of port of thiamin can be accomplished by both
pyruvate decarboxylase and transketolase active and passive processes. This was con-
due to an apoenzyme (7) or magnesium (8, 9) firmed in studies in rats in which intestinal
deficiency. The decrease in hepatic and cere- transport ofthiamin was shown to be biphasic
bral transketolase activity is accompanied by both by in vivo and in vitro methods (20). At
a parallel fall in thiamin concentrations in low or physiologic thiamin concentrations
the liver (10, 1 1) and brain (10). Furthermore, (< 1 .0 /LM), transport was a saturable, carrier-
since the transketolase activity correlates with mediated process requiring energy (Fig. 1 and
thiamin pyrophosphate concentrations (12), 2) while at higher or pharmacological thiamin
these findings suggest a lowering in the con- concentrations, transport was predominantly
centrations of thiamine pyrophosphate. In- by a passive, nonsaturable process (Fig. 3). It
deed, when hepatic thiamin pyrophosphate has also been shown that the rate of thiamin

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 2752 HOYUMPA

NET FLUX STUDIES

TRANSPORT AGAINST CONCENTRATION GRADIENT

S/M
RATIO

O.2pM 2OjjM
TH IAMIN CONCENTRATION

EFFECT OF VARIOUS INHIBITORS

O.2pM 2OpM

NORMAL

PT DNP NEM OUA PT DNP OUA

PT-PYRITHIAMIN DNP-DINITROPHENOL NEMN-ETHYLMALEIMIDE OUAOUABAIN

FIG. 1. Transmural net flux studies, in vitro, using evertedjejunal sacs incubated at 37 C with Kreb’s bicarbonate
buffer pH 7.4. Identical concentrations of ‘4C-thiamin hydrochloride were placed in the mucosal and serosal
compartments. Movement against a concentration gradient was deemed present if at the end of I hr incubation, the
concentration of labelled thiamin was greater in the serosal fluid, so that the serosal/mucosal concentration (S/M)
ratio was greater than the original 1.0. The top panel shows that 0.2 tM thiamin (open bar) was transported against
a concentration gradient (S/M ratio 1.5) while 20 sM thiamin (shaded bar) was not (S/M ratio, 1.0). The lower panels
compare the effect of various inhibitors on the net transmural flux of 0.2 eM thiamin (left) and 20 .tM thiamin (right).
These compounds inhibited thiamin in low, but not in high, concentration. Reproduced with permission (20).

transport is greater in the proximal than in centrations (20). Second, to traverse the lipid
the distal intestinal segment (Fig. 4). cell membrane, a water-soluble substance like
A tentative scheme of thiamin transport is thiamin requires special transport mecha-
shown in Figure 5. It can be seen that as nisms such as provided by mobile carriers. A
thiamin moves from the mucosal to the se- thiamin binding protein has been isolated
rosal compartment it encounters certain phys- and characterized in microorganisms (22-24),
icochemical barriers, and a number of events, but such a carrier protein has not yet been
some of which are still poorly defined, take identified in mammalian tissue. However, the
place. First, thiamin must get across the un- presence of such a carrier in rats is suggested
stirred water layer (21) adjacent to the cell by the observed saturation phenomenon at
membrane. Stirring of this water layer de- low thiamin concentrations (Fig. 2). Further-
creases its thickness, lowers the Km and fa- more, the competitive inhibition of thiamin
cilitates the transfer of thiamin in low con- transport exhibited by pyrithiamin (Fig. 2)

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 THIAMIN DEFICIENCY IN CHRONIC ALCOHOLISM 2753

z 250 NO PYRITHIAMIN

!!
c’J before subtracting passive component

200

I 50

I 00

01 0.2 03 04 05 0 20

THIAMIN CONCENTRATION (jiM)

FIG. 2. Unidirectional jejunal uptake of thiamin in vitro. Jejunal uptake rates in the absence of pyrithiamin
show saturation
(#{149}-#{149}) kinetics. The broken line (0- - -0) indicates uptake after subtracting the passive component,
calculated as the product of the permeability coefficient and the thiamin concentration. The addition of pyrithiamin,
2 zM (X-X) abolished the saturability. Each value represents the mean of 10 to 20 sacs. Reproduced with
permission (20).

5--NORMAL CONTROL (Nli) active, energy-requiring process which ena-

)O---x PYRITHIAMIN (N-7)
-

ADDED TO
bles the transfer of thiamin against a concen-
z INCUBATION MEDIA tration and electrochemical gradient (20).
Fourth, cyclic AMP has been shown to en-
N
hance transport of sodium and of certain
I- p > 05
amino acids (26), but it did not influence
‘1>- intestinal thiamin transport in rats (A. M.
Hoyumpa, Jr., and S. G. Nichols, unpub-
lished observations). Fifth, Na-K ATPase
(0_
2 which is located mainly in the basolateral
0-’
membrane (27) is believed to play an impor-
U
-J
0 tant role in active transport (28) by providing
0 energy through the hydrolyses of ATP. In
z
support of the role of Na-K ATPase in thia-
2
mm transport are the observations that va-
0 10 20 30 40 50
sopressin treatment in chicks increases intes-
THIAMIN CONCENTRTI0N (pM) tinal Na-K ATPasc activity and thiamin
transport (29) and that decreasing Na-K
FIG. 3.
Unidirectional jejunal uptake of high con-
centrations of thiamin, in vitro. Normal jejunal uptake
ATPasc activity by ethanol or ouabain cx-
(#{149}-#{149})
shows a linear relationship to thiamin concentra- posure is associated with a fall in thiamin
tions in the mucosal compartment. Addition of pyrithia- transport from the cell to the serosal com-
mm (X- - -X) causes no significant change in thiamin partment (see below).
uptake. Reproduced with permission (20).
In contrast to these characteristics of low
thiamin concentrations, the movement of
and other structural analogs (25) would sug- high concentrations ofthiamin is not affected
gest that these analogs vie with thiamin for by the thickness of the unstirred water layer,
common binding sites. Third, the adverse the presence of a structural analog, anoxia,
effect of anoxia, low temperature, and the hypothermia, or metabolic inhibitors. The
metabolic inhibitors dinitrophenol and N- part played by paracellular pathways in the
cthylmaleimide on the transport of low con- transport of thiamin across the intestine has
centrations of thiamin (Fig. 1) suggest an not been studied.

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 2754 HOYUMPA

TISSUE UPTAKE SEROSAL APPEARANCE

I-

z
0< 05 I-.-

a)
JEJUNUM 0”
0.:

o
0
aE
Ui0
0

-)

2 4

MINUTES MINUTES

FIG. 4. Comparison of thiamin tissue uptake (left panel) and rate of serosal appearance (right panel) between
jejunum and ileum in normal rats.

Thiamin

low concentration

high concentration

FIG. 5. Tentative scheme of intestinal thiamin transport. The different bamers to the transport ofthiamin in low
concentrations are represented. Thiamin crosses the unstirred water layer adjacent to the cell membrane and its
subsequent movement across the brush border membrane itself may involve a carrier protein. Analogs like
pyrithiamin compete with thiamin for binding sites on this carrier. Once inside the enterocyte, thiamin appears to be
phosphorylated, but is subsequently dephosphorylated as it leaves the cell. However, the role of phosphorylation in
thiamin transport is not completely settled. Dinitrophenol may inhibit mitochondrial oxidative phosphorylation; N-
ethylmaleimide may interfere with Na-K ATPase activity. Like ouabain, ethanol may impede thiamin transport
across the basolateral membrane by also inhibiting Na-K ATPase. In high concentrations, thiamin moves through
the enterocyte by simple diffusion and is not affected by these factors.

A number of studies have been carried out pounds in the form of tri-, di- (thiamin py-
to determine the role of phosphorylation in rophosphate) and monophosphate. The phos-
relation to thiamin transport. Thiamin pre- phorylated esters form as much as 60-80% of
sented at the mucosal side accumulates in the thiamin in the intestinal tissue. Subsequently
intestinal cell (30-34) as phosphorylated com- thiamin is dephosphorylated (35) and only

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 THIAMIN DEFICIENCY IN CHRONIC ALCOHOLISM 2755

free thiamin can be detected in the serosal unpublished observations). Thus, the dual
compartment by in vitro studies (36). This system of intestinal thiamin transport noted
may not be the case when circulation is intact, in rats was observed to apply also to humans.
since in vivo studies indicate that 57% of
Effect of ethanol
thiamin recovered in the portal blood is phos-
phorylated (34). Although thiamin undergoes Impairment of intestinal absorption of
phosphorylation in the cell, a number of ob- thiamin has been well-documented in a sub-
servations suggest that this process may not stantial number of chronic alcoholic patients
be critical for thiamin transport. First, phos- (47, 48). To understand the underlying mech-
phorylation of thiamin is not influenced by anism(s) of thiamin malabsorption in alco-
sodium lack, whereas thiamin transport is holism, the acute and chronic effects of
dependent on sodium (20, 34, 37, 38). Second, ethanol on thiamin transport, on Na-K ATP-
thiamin uptake proceeds at a decreasing rate ase activity, and on membrane fluidity were
along the intestinal tract, with the rate of studied in rats.
uptake highest in the duodenum and lowest Acute effect. The acute intragastric admin-
in the ileum, while the distribution of thiamin istration of ethanol, 50 to 750 mg/100 g body
pyrophosphokinase (the enzyme responsible weight, to rats reduced the absorption of low,
for phosphorylation) along the digestive tract but not of high, concentrations of thiamin
does not parallel the rate of thiamin transport (49). Once attained, this effect of ethanol was
(34). Third, the activity of thiamin pyrophos- not made worse by a further increase in the
phokinase is localized mainly in the soluble ethanol dose, and it was reversible as ethanol
cell fraction and scarcely detected in the disappeared from the blood stream. More-
brush border membrane which is the princi- over, it was unrelated to changes in osmolality
pal site of thiamin uptake. Fourth, thiamin or to any structural alterations of the intes-
transport may be dissociated from phospho- tinal mucosa. In vitro studies also showed
rylation in the isolated hcpatocyte ( 17). Fi- that ethanol inhibited the net transmural flux
nally, mutant strains of Escherichia coli which of thiamin in low, but not in high, concentra-
arc incapable ofphosphorylating free thiamin tions (Fig. 6). Subsequent in vitro studies
nevertheless maintain their ability to trans- localized the ethanol site of action. The up-
port thiamin (39). take of thiamin into the intestinal epithelial
Although the information gathered from cells was unimpeded by ethanol, but the
studies in animals and microorganisms pro- movement of low concentrations of thiamin
vide some useful insight into thiamin trans- (0.2 and 0.5 /iM) from the cells to the serosal
port in general, their relevance and applica- compartment was significantly impaired (Fig.
bility to man require confirmation. In the 7A). In contrast, the transport of high con-
past, in vivo studies in man have failed to centrations of thiamin (20 and 50 jiM) was not
define the precise kinetics of intestinal trans- affected (Fig. 7B), in keeping with the dual
port of thiamin (40-45). We have recently system ofthiamin transport. It was also noted
studied the uptake of thiamin by the small that ouabain, a known inhibitor of Na-K
intestinal mucosa obtained during endoscopic ATPase, exerted a similar effect on thiamin
examination. The results (A. M. Hoyumpa, transport with respect to its cellular uptake
Jr., R. Strickland, J. Schechan, G. Yarbor- and exit; this finding suggested that the im-
ough, and S. Nichols, unpublished data) in- pairment of thiamin exit from the cell may
dicate that at low thiamin concentrations (< be related to ethanol inhibition of Na-K
2.0 LM), uptake is a saturable phenomenon ATPase activity in the basolateral membrane.
and is diminished by pyrithiamin, anoxia and Effect of acute ethanol exposure on Na-K
sodium lack. Phosphorylation and accumu- A TPase. To determine the effect of ethanol
lation ofthiamin (0.2 tM) in intestinal mucosa directly on Na-K ATPase activity, brush bor-
were also observed by Rindi and Ferrari (46) dcr and basolatcral membranes were isolated
in human surgical specimens. In contrast, at from rat enterocytes and Na-K ATPase activ-
higher thiamin concentration (5 to 50 LM) ity was measured (27). Na-K ATPase activity
intestinal mucosal uptake exhibits first order was noted to reside mainly in the basolateral
kinetics (A. M. Hoyumpa, Jr., R. Strickland, membranes. In vitro exposure of the basolat-
J. Sheehan, G. Yarborough, and S. Nichols, eral membrane to 0.5 M ethanol reduced Na-

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 2756 HOYUMPA

K ATPase activity by at least 50% (Fig. 8) ethanol was administered by gavagc one hour
and exposure to a range of ethanol concen- before the isolation of the membranes and
trations (0. 1 to 1.0 M) produced a dose-depen- measurement of Na-K ATPase (26). Further-
dent but nonlinear inhibition (not shown). more, the fall in Na-K ATPase activity was
This inhibitory action was reproduced when accompanied by a decrease in the rate of
thiamin transport from the cell interior to the
serosal compartment (Fig. 9). Thus, it is cvi-
CONTROL ALCOH0L

RATIO
dent that ethanol inhibits both Na-K ATPase
20
activity and serosal transport (exit) of small
quantities of thiamin. However, whether this
association is causal or casual remains to be
established. It is also pertinent to examine in
the future whether ethanol interferes with
thiamin phosphorylation and dephophoryla-
tion mechanisms.
Effect of chronic ethanol ingestion. The rel-
evance of the above observations, obtained
with single doses of ethanol given to normal
rats, to the pathogenesis ofthiamin deficiency
O2pM 2OpM
in chronic alcoholism in man is uncertain.
THIAMIN CONCENTRATION
Therefore, the influence of chronic ethanol
FIG. 6. Effect ofalcohol (ethanol) on net transmural
administration on thiamin transport was
flux ofthiamin in vitro. Ethanol 2.5% was placed in both
mucosal and serosal compartments. As shown in the left studied. Rats were fed an ethanol-containing
panel, ethanol inhibited the movement of thiamin in low liquid diet as described by Dc Carli and
concentration (0.2 LM) so that the serosal/mucosal con- Lieber (50) for 6 to 8 weeks. Thiamin trans-
centration ratio was reduced from the control value of
port was measured using everted intestinal
I .5 (open bar) to I .0 (hatched bar). In contrast, as shown
segments and correlated with Na-K ATPase
in the right panel, ethanol had no effect in the net flux of
thiamin in high concentration (20 riM). Reproduced with activity in the basolateral membrane (13).
permission (49). Results indicated that chronic ethanol feed-

B. HIGH THIAMIN CONCENTRATION

300C

LI CONTROL
- 2S000ALCOHOL
. p>O5

3 2000

500

‘ p>.O5

000

I ,

I- 500

II JL.

O.2jiM O.5pM 2OpM 5OpM

THIAMIN CONCENTRATION THIAMIN CONCENTRATION

FIG. 7. Effect of alcohol (ethanol) on the transport of thiamin from the intestinal epithelium to the serosal
compartment (serosal exit). Low thiamin concentrations (0.2 and 0.5 tM) are shown in the left, high concentrations
(20 and 50 /LM) on the right. Alcohol inhibited the transport of low, but not of high, thiamin concentrations.
Reproduced with permission (49).

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 THIAMIN DEFICIENCY IN CHRONIC ALCOHOLISM 2757

ing impaired neither thiamin uptake nor se- ethanol concentrations in the plasma and
rosal exit when the ethanol concentrations in intestinal lumen were raised to 185 and 318
the plasma and intestinal lumen were 40 and mg/ 100 ml by an additional single intragas-
39 mg/lOO ml, respectively. Similarly, Na-K tric dose of ethanol, 250 mg/lOO g body
ATPase activity in the basolateral membrane weight, the exit of thiamin (0.2 and 0.5 /.LM)
was unaffected (Fig. 10). However, when the across the serosal membrane was significantly
decreased along with a corresponding reduc-
tion ofthe basolateral membrane Na-K ATP-
asc activity (Fig. 11). These data suggest that
the inhibition of thiamin transport is depen-
>-c
dent more on the systemic ethanol concentra-
>a tions present rather than on the duration of
p- 0
exposure to ethanol and that thiamin mal-
absorption in this model may be intermittent.
That thiamin malabsorption may result from
chronic ethanol ingestion was also shown by
others (5 1). Any intermittent malabsorption
of thiamin would clearly become more sig-
nificant if associated with marginal thiamin
intake as is often the case with alcoholic
JEJUNUM ILEUM patients.
FIG. 8. Effect of ethanol 0.5 H on basolateral mem- Ethanol and membranefluidity. An optimal
brane Na-K ATPase activity. fluidity or microviscosity of the cell mcm-

IS

-J
0
IO z
I
U’

% 5
-J
a.

‘a
I.--.

-J
0
>- 2
I-.
I
U
t.2100 z
U

a...
i-c
_J

-J

z- U
I-
z

ETHANOL DOSE
(mg/bOG B.W.)
FIG. 9. Effect of acute ethanol ingestion on thiamin transport across the basolateral membrane to the serosal
compartment and on the basolateral membrane Na-K ATPase activity. The study shows a correlation between the
impairment ofthiamin transport (A) and the fall in Na-K ATPase activity (B) I hr after the intragastric administration
of ethanol 50 to 750 mg/lOO g. The ethanol concentrations in plasma (C) and intestinal lumen (D) are also shown.
Reproduced with permission (27).

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 .-.PAIR-FED CONTROL

2758 HOYUMPA

A THIAMIN TRANSPORT B. Na-K ATPase

- 2C
UJE o--0CHRONIC ETHANOL
ZN-)

a:
0QJ
Q_ 0
(flU ,
Z
a: - IC

OE
ZcCo
- UJO
w;::
O(f)
,Alrr p>O5
? (r’.9-ISporsl
OL)
I I I
Oa
0.2 0.4 0.6 0.8
THIMIN CONCENTRATIONS FED ETHANOL
(jM) CONTROL

FIG. 10. Lack ofeffect ofethanol feeding for 6 to 8 weeks on thiamin transport across the serosal membrane (A)
and on the basolateral membrane Na-K ATPase activity (B). Ethanol concentrations in the plasma and intestinal
lumen were low (see text). Reproduced with permission (13).

A THIAMIN TRANSPORT B. Na-K ATPase

C 2C >-

:: PAIR-FED CONTROL >-

Zr))

I-a c: ETHANOL
U

a a 150
0 p<.O25
Q-LU

.C_J
‘

I
a:Z IC 100

p<.OOI
ZUO

..(D 5 50
100 22
OL) oE
0c - - - UL.L_O
0.21jM 0.5pM JEJUNAL BASOLATERAL
THIAMIN CONCENTRATION MEMBRANES

FIG . 1 1 . Effect of chronic ethanol feeding (6 to 8 weeks) plus an acute dose of intragastric ethanol, 250 mg/l00
g, on thiamin transport across the serosal membrane (left) and on basolateral membrane Na-K ATPase activity
(right). Reproduced with permission (13).

brane is required for normal cell functions. der and basolateral membranes in a dose-
Since Na-K ATPase is a membrane protein, dependent manner, similar to the data ob-
it is possible that the decrease in its activity tamed in mouse erythrocytcs and brain mem-
may be related to changes in its microenvi- branes (53). In contrast, membranes obtained
ronment. In addition, physical perturbation from rats fed ethanol (Dc Carli-Lieber diet)
of the membrane bilayer may so alter the for 12 weeks did not alter membrane fluidity,
disposition of transport channels as to inter- a finding also noted in the erythrocyte of
fere with the transport process. Therefore, the mice exposed to ethanol for 8 days (54).
physical state of the cell membrane was as- However, the acute addition of ethanol in
sessed by determining membrane fluidity by vitro to membranes from rats on the chronic
electron paramagnetic resonance (52). The ethanol diet produced a dose-dependent in-
spin label used, N-oxyl 4’, 4’-dimethyloxazo- crease in the fluidity of brush border and
lidine derivative of 5 ketostearic acid, moni- basolateral membranes (52). These fluidity
tors the region of the polar heads close to the data obtained by different groups of investi-
water-lipid interface. Both the enterocyte gators echo the findings on thiamin transport
brush border and basolateral membranes and Na-K ATPase activity with respect to the
were examined. Acute in vitro exposure to effect ofacute and chronic ethanol treatment.
ethanol, 0. 1 to 1 .0 M, increased the fluidity Moreover, it is believed that chronic ethanol
(decreased microviscosity) of the brush bor- exposure leads to membrane adaptation. This

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 THIAMIN DEFICIENCY IN CHRONIC ALCOHOLISM 2759

may explain why no abnormality in trans- in the pathogenesis of thiamin deficiency in

port, ATPase activity, and fluidity was de- chronic alcoholism. It is also likely that sev-
tectcd. The adaptive change may be charac- eral of these mechanisms may be involved
terized by an increase in the cholesterol con- concurrently in an individual patient, al-
tent on the membrane and a reduction in the though it may be difficult to determine the
proportion of polyunsaturated fatty acids exact contribution of each factor.
(55). These modifications in the lipid com-
position of the membrane tend to increase References
membrane viscosity and to minimize the flui-
1. LEEVY, C. M., H. BAKER, W. TEN HovE, 0. FRANK
dizing influence ofcthanol. Although the per- AND G. R. CHERRICK. B-complex vitamins in liver
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