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vol. 4/2 (1974)

Birkhfiuser Verlag Basel


Protection against Acetaldehyde Toxicity in the Rat by L-Cysteine,

Thiamin and L-2-Methylthiazolidine-4-carboxylic Acid 1)
from US Veterans Administration Hospital, Coatesville, Pennsylvania 19320, and The Departments of Psychiatry and
Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA


Acetaldehyde is 10-30 times more toxic than ethanol

and has been implicated in alcoholic cardiomyopathy. Its oral
LD50 and L D 9 0 Litchfield-Wilcoxon values weri~ found to
be 15.0 (14.4-15.6) m M / k g and 18.0 (15.5-20.5) mM]kg,
respectively. Protection against acetaldehyde lethality was
obtained by oralintubation of test compounds 30-45 minutes
prior to oral intubation of 18 mM]kg of acetaldehyde. At
2.0 mM]kg, survival after 24-72 hours with L-cysteine free
base(FB) was 80 %; with L-2-methylthiazolidine-4-carboxylic
acid (L-MTCA), 75 %; with thiamin 9 HCI, 90 %; and only
10 % with saline control. At 0.3 mM/kg, thiamin- HCI gave
virtually no protection (13 % survival). The combination of
L-cysteine FB plus thiamin. HCI, each at 2.0 mM/kg, gave
100 % survival. The oral LD 50 dose (Litchfield-Wilcoxon) in
m M / k g for L-cysteine FB was 15.6 (14.8-16.4); for L-MTCA,
17.9 (17.0-18.8), and for thiamin - HCI, 11.0 O0.4-11.6).
The ratio of toxic dose-protective dose of the fi~st two compounds warrants further study of them in combination with
thiamin as possible protective agents against the chronic
toxicity of acetaldehyde associated with heavy ethanol intake
and heavy smoking.

Increased interest has developed in recent

years in the toxicity of acetaldehyde for a number
of reasons: (a) it is a key intermediate in the
metabolism of ethanol [ 1] and occurs in the vapor
phase of cigarette smoke [2]; (b) it is 10-30 times
more toxic than ethanol [3, 4]; (c) it is believed
to give rise to the toxic effects of the disulfiramethanol reaction [3, 4] and related reactions [5];
and (d) it depresses Coenzyme A (CoA-SH)
activity in brain and liver [6]. Lastly, it possesses
sympathomimetic activity and has been implicated in alcoholic cardiomyopathy by virtue of its
release of catecholamines [7, 8]. In this regard,
it has been suggested that the continuous metabolic generation and presence of acetaldehyde in
the body at above normal levels as the result of
chronic high alcohol intake together with heavy

smoking (the two frequently occur in associationcould play a role in the development of cardiot
vascular disease [9]. From these observations, iis evident that studies of protection against acetal)
dehyde toxicity and lethality (preferably by naturally-occurring metabolites used in pharmacological doses) are very much in order.
Currently, on biochemical and biological
grounds there is a good basis for such studies.
On biochemical grounds, protection against
acetaldehyde might be obtained with two naturally-occurring compounds, L-cysteine and thiamin, either of which could complex with it by
way of free sulfhydry! (-SH) groups to eventually form relatively non-toxic compounds. Lcysteine could complex with acetaldehyde to
form a hemiacetal which would then cyclize to
form L-2-methylthiazolidine-4-carboxylic acid
(L-MTCA) [10, 11]. L-MTCA might then serve
as a non-toxic metabolic detoxification product
as well as a protective agent per se by generating
free intracellular (-SH) groups more effectively
as suggested by DEBEu et al. [11]. Thiamin as
cocarboxylase (pyrophosphate form) could complex with acetaldehyde by way of pyruvic oxidase
to give rise eventually by way of lipoic acid to
acetyl Coenzyme A [12]. On biological grounds,
both L-cysteine and L-MTCA could protect
against the lethal pulmonary edema induced by
acetaldehyde by way of free or latent (-SH)
groups in a manner similar to that reported
against the lethal pulmonary edema induced by
thiourea compounds [11, 13, 14].
1) Supported by US Veterans Administration (Project
Nos. 8078-01 and [8078] 2-70).
2) Address reprint requests to Dr. Herbert Sprince, VA
Hospital, Coatesville, Pennsylvania 19320, USA.


Acetaldehyde Toxicity in the Rat

It is t h e p u r p o s e o f this p a p e r to p r e s e n t
d a t a o n t h e p r o t e c t i v e a c t i o n o f L-cysteine free
b a s e (FB), t h i a m i n . H C I , a n d L - M T C A a g a i n s t
a c e t a l d e h y d e t o x i c i t y a n d to c o m p a r e t h e p r o t e c t i v e d o s e levels w i t h t h e t o x i c d o s e levels o f
these compounds.

14, 16, 17, 18, 20 and 22. The calculated oral LD90 dose
level (Litchfield-Wilcoxon) was further checked experimentally in 50 rats 90 5 days old and weighing 365
20 g. The experimental oral LD90 thus determined was
the value taken as the standard lethal dose used hereafter
in this study. All calculated and experimental LD50 and
LD90 values are presented under Results. Reasons for
choice of the LD90 dose as the standard lethal dose are
presented under Discussion.

Materials and methods


Rats used: strain, sex, age, and weight

For this study, Carworth Farms CFE strain male
albino rats 90 5 days old and weighing 365 20g
were deprived of food, but not water, overnight and reweighed the next morning just prior to test. CFE rats of
this age and weight were chosen because their growth
rate decreases markedly at approximately 90 days of age
(Carworth Farms data), a desirable stage for experimentation with young mature rats to insure uniformity and
reliability in administering desired dose levels.

Preparation of test compounds

Solutions or fine suspensions of test compounds
were freshly prepared before use in physiological (0.9%)
saline purged beforehand with nitrogen gas to prevent
undesirable oxidation of these compounds. Dilutions
were then made to concentrations suitable for oral intubation of required dose levels at convenient volumes
(1-2.5 ml). Dose levels used were expressed as millimoles/
kilogram (mM/kg). Acetaldehyde was always freshly
distilled just before use. L-cysteine FB and L-MTCA were
intubated as fine suspensions at the dose levels tested.
Combinations of test compounds were prepared as single
t - M T C A was prepared by a modification of the
method of DEBEu et al. [11]. Thirty grams of L-cysteine
were dissolved in 250 ml of distilled water (purged of dissolved oxygen by gassing with nitrogen) to form an
opalescent solution. Fifteen ml of freshly-distilled acetaldehyde were added (final pH = 5.2), the solution stirred
for 10 minutes, heated slowly to 75~ under a reflux condenser, and filtered while hot. The clear filtrate was evaporated to a white slurry (60 ml), warmed, transferred to
a beaker with a minimum volume of water, and placed
in the refrigerator (4~
overnight. Next morning the
precipitate was filtered, washed with 80~oo ethanol, and
dried to constant weight at 60~ in a vacuum oven. The
final product (weighing 32.8 g, approximately 90~oo yield)
was a white amorphous powder with a melting point
(determined by Fisher-Johns apparatus) of 162-163~
which was the same as that shown by a custom-made
sample of L-MTCA purchased from the Eastman Kodak
Company, Rochester, New York and that reported by
DEB~Y et al. [11].
(c) Standardization of lethal dose levels of acetaldehyde
(LD 50 and LD 90 values)
Oral LD50 and LD90 dose levels of acetaldehyde,
calculated by the Litchfield-Wilcoxon method [15], were
determined using 96 CFE rats (12 rats/group) and the
following dose levels of acetaldehyde (in mM/kg) : 10, 12,


Test procedure for protection experiments

For protection tests, 45 rats were divided into nine
equal groups (5 rats/group). Tests were repeated at least
in triplicate, i.e. on 3 consecutive days, so that the minimum total number of rats tested for any given group was
15 rats. In some cases, many more rats were used for a
given group. Test compounds were intubated orally before acetaldehyde intubation. Details of the test procedure and data obtained are presented in Table 1.
(e) Toxic dose levels of L-cysteine (FB), L-MTCA and
thiamin - HCI
To determine toxic dose levels of L-cysteine (FB),
L-MTCA and thiamin- HC1 per se, the oral LD50, LD 10,
and LD 1 were obtained by the Litchfield-Wilcoxon method [15], using the following dose levels (in mM/kg): for
L-cysteine (FB), 10, 12, 14, 16, 18 and 20; for L-MTCA,
10, 12, 14, 16, 17, 18, 20 and 25; and for thiamin - HC1,
4, 6, 8,10,11,12, 14 and 16. Fifteen rats were used for each
dose level tested. Findings are presented under Results.


A c e t a l d e h y d e : L D 50 and L D 90 values
T h e o r a l - 2 4 h o u r L D 50 a n d L D 9 0 v a l u e s
o f freshly distilled a c e t a l d e h y d e in m a l e C F E
rats, 90 =k 5 d a y s old, w e i g h i n g 365 i 20 g,
fasted o v e r n i g h t w e r e o b t a i n e d a n d c a l c u l a t e d b y
the L i t c h f i e l d - W i l c o x o n m e t h o d w i t h 19/20 c o n fidence limits [15] to be as f o l l o w s : L D 5 0 = 15.0
(14.4-15.6) m M / k g e q u i v a l e n t to 661 (634-687)
m g / k g a n d L D 9 0 = 17.8 (15.5-20.5) m M / k g
e q u i v a l e n t t o 784 ( 6 8 3 - 9 0 3 ) m g / k g . A d d i t i o n a l l y ,
w i t h an e x p e r i m e n t a l d o s e o f 18.0 m M / k g in
50 rats, t h e 24 h o u r l e t h a l r e s p o n s e was 45 rats
d e a d o u t o f 50 tested. H e n c e , 18.0 m M / k g
( = 793 m g / k g ) o f a c e t a l d e h y d e was u s e d herea f t e r as t h e s t a n d a r d l e t h a l d o s e ( o r a l 2 4 - h o u r
L D 90) in o u r p r o t e c t i o n e x p e r i m e n t s .
Toxic manifestations of acetaldehyde were
c h i e f l y r e s p i r a t o r y distress, g a s p i n g , a n d an
a n e s t h e t i c - l i k e p a r a l y s i s w i t h loss o f r i g h t i n g
reflexes as r e p o r t e d b y o t h e r s [3]. C h a r a c t e r i s t i cally, the a n e s t h e t i c ( h y p n o t i c ) effect o f acetald e h y d e d e v e l o p e d v e r y q u i c k l y after its i n t u b a t i o n ( w i t h i n 3 - 1 0 m i n u t e s ) a n d was o f s h o r t d u r a t i o n (5-15 m i n u t e s ) . T h e a n i m a l s a p p e a r e d to
r e c o v e r v e r y q u i c k l y a n d t o be n o r m a l f o r a b o u t

Acetaldehyde Toxicity in the Rat


2-3 hours. Eventually, respiratory distress, stupor, and death ensued. Lethality was 54% in
3 hours and 90% in 24 hours (see Table 1), an
observation pointing to a delayed toxic effect.
Delayed lethality generally (but not always)
occurred in rats which had appeared to recover
from the anesthetic effect.


tion against the anesthetic effect generally resulted in protection against lethality. In separate
experiments (not shown in Table 1), protection
effects of L-cysteine FB and L - M T C A were not
appreciably increased at 3.0 m M / k g and were
decreased at 1.0 m M / k g . Thus, a dose o f 2.0 m M /
kg was the optimal protective dose o f these comp o u n d s under our test conditions.

Protection studies

Protection data are presented in Table 1.

F r o m Table 1, it is obvious that at 2.0 m M / k g
L-cysteine FB, L-MTCA, and thiamin 9 HC1 per
se offer considerable protection against the
anesthetic and lethal effects o f acetaldehyde
(18.0 mM/kg), whereas at 0.3 m M / k g thiamin 9
HC1 per se has very little, if any, effect. Thus,
after 24 hours, survival with L-cysteine FB was
80%, with L - M T C A 75%, with thiamin 9 HC1
90%, and only 10% with the saline control. In
combinations with thiamin 9 HC1 at 2.0 m M / k g ,
complete protection, i.e. 100% survival was
obtained with L-cysteine (Combination F), but
not with L - M T C A (Combination G). Similarly,
in combinations with thiamin. H C I at 0.3 mM/kg,
some enhancement of protective action was discernible with L-cysteine FB (Combination H),
but not with L - M T C A (Combination I). Protec-

(c) Toxic dose levels of L-cysteine FB, L-MTCA

and thiamin. HCI per se
Oral-24 h o u r L D 50, L D 10, und L D 1 values
o f these c o m p o u n d s are presented in Table 2. The
ratio T D / P D is at best only a measure o f the
relative safety o f the optimally protective dose
level. More sophisticated measurements requiring m u c h greater numbers of animals, such as
the therapeutic index ratio [16] or the standard
safety margin ratio [16] are b e y o n d the scope of
this p a p e r .
Toxic manifestations o f these c o m p o u n d s
in rats were as follows. With L-cysteine FB, there
was depressed, irritable, somnolent behavior
characterized initially by a hunched standing position which developed into a restless reclining
position after 2 hours. At the same time, characteristically an elevated tail twitch developed with

Table 1
Protective action of L-cysteine FB (free base), thiamin 9HCI, and L-2-methylthiazolidine-4-carboxylic acid (L-MTCA)
against anesthetic and lethal effects of acetaldehyde (AcH) in the rat.
Compounds tested


3-10 minutes

3 hours

24 hours

72 hours

(oral dose)

(oral dose)

~ anesthetized

~ dead

~ dead

~ dead

(A) Saline control

03) L-cysteine FB
(2.0 mM/kg)
(2.0 mM/kg)
(D) Thiamin- HC1
(2.0 mM/kg)
(E) Thiamin- HCI
(0.3 mM/kg)

18.0 mM/kg
18.0 mM/kg

96 (48/50)
20 (5/25)

54 (27/50)
8 (2/25)

90 (45/50)
20 (5/25)

90 (45/50)
20 (5/25)

18.0 mM/kg

25 (5/20)

5 (1/20)

25 (5/20)

25 (5/20)

18.0 mM/kg

10 (2/20)

0 (0/20)

10 (2/20)

10 (2/20)

18.0 mM/kg

73 (11/i5)

53 (8/15)

87 (13/15)

87 (13/15)

18.0 mM/kg
18.0 mM/kg
18.0 mM/kg
18.0 mM/kg

5 (1/20)
0 (0/15)
13 (2/15)
33 (5/t5)

0 (0/20)
0 (0/15)
0 (0/15)
27 (4/15)

0 (0/20)
13 (2/15)
13 (2/15)
33 (5/15)

0 (0/20)
20 (3/15)
13 (2/15)
33 (5/15)

Combinations of above
(F) (B + D)
(G) (C + D)
(H) (B+E)
(I) (C + E)

Compounds tested were intubated orally 3045 minutes prior to oral intubation of 18 mM/kg of AcH (LD90 dose).
Doses are expressed in millimoles/kilogram (mM/kg). After intubation, rats were observed over a 24-72 hour
period for anesthetic effects (loss of elevation and righting reflexes) and lethal response (deaths). Figures in parentheses = No. rats anesthetized or dead-No, rats tested. Anesthesia (loss of righting reflexes) with AcH generally
occurred within 3-10 minutes and lasted for 5-15 minutes. Deaths were recorded after 3, 24, and 72 hours.


Acetaldehyde Toxicity in the Rat

some resemblance to the Straub-Herrman tail

reaction in mice [I7] and was associated with
urinary and fecal smearing. Eventually stupor
developed and deaths occured within 8-10 hours
at the higher dose levels tested. Tremors and
seizures were observed before death in a few
instances. With L - M T C A , the animals remained
initially alert and active with good body tone.
Within 3-6 hours, they became immobilized with
signs of muscular rigidity. Myoclonus developed
in a few instances. Urinary and fecal smearing
was not prominent, nor was the tail twitch noted
above observed. Eventually, respiratory distress
and stupor developed. Deaths occured mainly
over a 10-24 hour period at the higher dose levels
tested. With thiamin - HCl, marked tremors developed within 5-10 minutes. These persisted for
another 5-10 minutes and were followed by a
characteristic jumping behavior for about 1-3
minutes. Soon thereafter, the animals became
limp. Death occurred within 1 5 4 5 minutes after
intubation from respiratory failure as observed
by others [18].

pecially important in this regard was the age

factor, since in exploratory experiments (not presented above), we found the L D 9 0 of acetaldehyde for 60, 90, and 200 day old CFE rats to
be 22, 18, and 14 m M / k g respectively. Thus,
acetaldehyde was considerably less toxic in younger rats than in older rats, a finding similar to
that reported for paraldehyde [19]. The rapid
utilization of acetaldehyde in vivo could also
explain why the L D 90 dose was more effective
than the L D 50 dose in demonstrating protection
against acetaldehyde toxicity. Noteworthy, too,
is the difference in the oral L D 50 value for acetaldehyde reported by SMYTH et al. [20] and most
frequently quoted in the literature as being 1930
(1620-2240) mg/kg in comparison with our carefully standardized value found to be 661 (634687) mg/kg. (Expressed as mM/kg, these values
are 43.8 (36.8-50.9) and 15.0 (14.4-15.6) respectively.) In this regard, it is important to note that
we conducted our toxicity tests on CFE rats
weighing 365 + 20g fasted overnight whereas
SMYTHet al. [20] used Wistar rats weighing 90-120g
not fasted overnight. These factors and the age
difference probably account for this difference in
LD 50 values.
Concerning protection experiments, thiazolidine ringformationbyaldehyde-thiolcompounds
has already been implicated in biochemical reactions [21]. It is known to occur non-enzymatically
at neutral p H and r o o m temperature [22]; its
formation in vitro has been reported to alter the
equilibrium of the alcohol dehydrogenase reac-


In this study, we found it essential to use

freshly distilled acetaldehyde and to standardize
very carefully its toxic dose in relation to rat
strain, sex, age, weight, and overnight fast. Such
standardization was necessary since acetaldehyde
is known to be rapidly metabolized in vivo [1,3, 4],
an effect which can give rise to variable results if
test conditions are not carefully controlled. EsTable 2

Toxic dose levels of L-cysteine FB, L-MTCA and thiamin 9HC1 per se in the rat.
Compound tested
L-cysteine FB
LD 10
LD 1
LD 50
LD 10
LD 1
Thiamin. HC1
LD 10
LD 1




15.6 (14.8-16.4)
13.8 (12.0-15.9)
11.5 (8.7-15.2)

1890 (1793-1987)
1672 (1454-1926)
1393 (1054-1842)


17.9 (17.0-18.8)
14.9 (13.1-17.0)
12.4 (9.7-15.8)

2635 (2502-2767)
2193 (1928-2502)
1825 (1428-2325)


11.0 (10.4-11.6)
8.6 (7.4-10.1)
6.6 ( 5.0- 8.8)

3710 (3508-3912)
2901 (2496-3407)
2226 (1686-2968)


LD values above are oral-24 hour Litchfield-Wilcoxon values obtained with male CFE rats, 90 4- 5 days old,
weighing 365 20 g and fasted overnight.
*) Ratio TD/PD = toxic dose-protective dose (2.0 mM/kg from Table 1). It measures the relative safety, i.e. the
number of times greater the toxic dose is than the optimally protective dose.


Acetaldehyde Toxicity in the Rat

tion [23]; and its formation in viva has been

suggested as a detoxification mechanism for
aldehydes [11]. Therefore, under our test conditions, there is a good possibility (yet to be conclusively demonstrated) that acetaldehyde detoxification in viva by L-cysteine FB is by way of
thiazolidine formation, namely, L-MTCA. Of
further interest is the observation that L-MTCA
per se also protects against acetaldehyde toxicity,
indicating that it is not merely an inert detoxification product arising from the chemical reaction of L-cysteine FB with acetaldehyde in the
gastrointestinal tract. A possible explanation for
this finding may reside in the suggestion of DEBEY et al. [I I] that L-MTCA serves to transport
'frozen sulfhydryl groups' in extracellular fluids
to liberate free - S H groups intracellularly.
From data in Table 2, several points are
worthy of mention. Thus, oral LD 50 values of
L-cysteine FB and L-MTCA under carefully controlled conditions are presented for the first time,
as far as this author has been able to ascertain
from the literature. The only other toxicity report
found was for L-MTCA, the LD 50 dose subcutaneously in mice being reported as 300-400 mg/
kg [24]. Noteworthy, too, is the oral LD 50 of thiamin 9 HC1 found in this study to be 3710 (35083912) mg/kg which is considerably less than
9500 mg/kg most frequently quoted in the literature as the oral LD 50 for thiamin- HC1 in the rat
[18]. Again, strain, age, weight, and sex of the test
animals are factors to be considered. From
Table 2, it is also evident that in rats the LD 1
toxic dose levels of L-cysteine FB or L-MTCA
per se are approximately 6 times greater than
their respective optimally protective dose levels
against acetaldehyde toxicity under our test conditions. Strangely enough, the LD 1 of thiamin 9
HC1 is only about 3 times greater than its optimally protective dose level indicating that thiamin. HCI is about twice as toxic as L-cysteine FB
or L-MTCA. However, the T D / P D ratios of
L-cysteine FB and L-MTCA, appear to be of
sufficient magnitude to warrant further study of
these compounds in combination with thiamin
as possible protective agents against the chronically adverse effects of acetaldehyde postulated
to be involved in the development of alcoholic
cardiomyopathy [7, 8]. A rat model for testing
the protective action of such compounds is now
available [25, 26], and future studies along these
lines are contemplated.
Received 20 January 1974.

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Acetaldehyde Toxicity in the Rat

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