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EC number: 204-815-4
CAS number: 126-97-6
The mortality and the signs of systemic toxic observed in the oral acute or repeated dose toxicity studies seems primarily linked to the inhibition of the β-oxidation of fatty acids. This inhibition induced secondary effects like a decrease of blood glucose, liver glycogen content, blood and hepatic ketone bodies and liver acetyl-CoA and an increase of plasma free fatty acids and liver triglycerides and acyl-CoA and an enhancement of hepatic pyruvate. The fatty liver induced by mercaptoacetate was mainly due to an inhibition of acyl-CoA dehydrogenase activity and consequently to a marked depression of the β-oxidation pathway. Fasted animals appeared to be more sensitive to the toxic effects than non-fasted animals.
In the divers acute or repeated dose toxicity
studies (OECD # 408, 414, 416 and 421) performed by oral route with
mercaptoacetic acid and/or its salts, signs of systemic toxic (including
mortality), increase of food consumption and/or perturbation of some
biochemical parameters related to the fatty acids oxidation were
observed. It is suggested that the most probable mechanism of toxicity
was linked to the inhibition of the β-oxidation of fatty acids as
Effects of mercaptoacetate on glycemia
Mercaptoacetate has been proved to have an
action on blood glucose regulation (Freemanet al., 1956).
Respectively, six hours after i. v. (175 mg/kg bw) or i. p. (150 mg/kg
bw) treatments with sodium mercaptoacetate, rabbits and rats presented a
significantly reduced blood sugar concentration (> 50%), sometimes
leading to death. Since the LD50greatly increases in
glucose-treated rats (3.4 to 4.4 fold), it is very likely that animals
died from hypoglycaemia. Five hours after i. p. treatment (0.04 ml/g of
5% glucose solution ± 630 mg/kg bw sodium mercaptoacetate), the average
liver glycogen found in treated mice was significantly reduced (>70%)
indicating glycogenolysis due to mercaptoacetate. There was no
significant difference in muscle glycogen of treated and untreated
animals (3 mL of 50% glucose solutionper os± 300 mg/kg bw sodium
mercaptoacetate i. p.). In diabetic rats treated with mercaptoacetate,
the water intake, the urine volume and the urinary sugar decreased,
suggesting that mercaptoacetate was not acting by increasing insulin
secretion. There appears to be a rise then a fall in blood sugar in
diabetic rabbits after treatment with mercaptoacetate (300 mg/kg bw i.
In a recent study (Davies, 2010c), not yet
finalized at the time of registration, it appeared that fasted animal
are more sensitive to the toxic and hypoglycemic effects of
mercaptoacetate than non-fasted animals. In fasted animals, an initial
rise of the glycemia is followed by a severe hypoglycemia until the
re-feeding of the animals. In the non-fasted animals, no initial rise
was observed and the hypoglycemia was moderate compared to fasted
animals. The initial glucose rise in the fasted animals suggest that
mercaptoacetate stimulate the glycogenolysis, then when the glycogene is
consumed, the glycemia decreased. The administration of glucose to
fasted animals prevents the blood glucose decrease. It could explain why
significant effects on blood glucode, ß‑hydroxybutyrate and/or
acetoacetate was observed in the 90-day oral study (Rousseau, 2010)
whereas no effect was observed in the 2-generation study (Davies 2010a).
In the 90-day study, the animal were fasted overnight before the blood
sampling, 5-6 hours after the treatment, in the 2-generation, the
animals were not fasted.
Effects of mercaptoacetate on the fatty
acid oxidation and liver enzyme activity
On the basis of the published results
(Nordmann and Nordmann, 1971; Sabouraultet al.,1976; Sabouraultet
al.,1979; Bauchéet al.,1981; Bauchéet al.,1982;
Bauchéet al.,1983.;Sabbaghet al.,1985; Schulz,
1987), there is no doubt that mercaptoacetate inhibited the
hepaticβ-oxidation of fatty acids resulting in a greater conversion into
triglycerides in the liver. As a result, ketogenesis was inhibited.
Intraperitoneal administrations (31 mg/kg bw
and 15 mg/kg bw, 3 hours later) of 2-mercaptoethanol (which is oxidized
to mercaptoacetate) causes a fatty liver, as shown by the highly
significant (p<0.01) increase of liver triglycerides (2.2x), accompanied
by a considerable increase of plasma free fatty acids (2.4x) and by
remarkable decreases in blood ketone bodies (acetoacetate –73% and
β-hydroxybutyrate –90%), 3 hours after the 2ndinjection.
A very significant (p<0.01) decrease of blood glucose (-35%) and liver
glycogen (-70%) content occurs at the same time(Nordmann and Nordmann,
1971; reliability 2).
It appears that mercaptoacetate administered
to female Wistar rats (45 mg/kg bw, i. p.) induced an increase of
hepatic triacylglycerol (2.7x at 3h and 13.7x at 24h) and blood free
fatty acids (3.9x at 3h and no effects at 24h), a decrease of blood
triacylglycerol (-30% at 3h and –48% at 24h) and phospholipids (-43% at
3 h and –18% at 24h) as well as a reduction in the hepatic ketone body
level (acetoacetate –52% at 3h and β-hydroxybutyrate –75% at 3h and –42%
at 24h). The large and early increase of blood free fatty acids reflects
most probably an enhanced peripheral fat mobilization, which is an
important factor in the pathogenesis of fatty liver (Sabouraultet al.,1976;
After mercaptoacetate administration (45
mg/kgbwi. p.) the hepatic levels of free CoA-SH and acetyl-CoA were
markedly decreased, falling to c. a. 20% of the control values. At the
same time, on the contrary, the hepatic acyl-CoA level was increased
(+120%), an effect which did not completely balance, however, the
reduction in free CoA-SH and acetyl-CoA concentrations. Moreover,
2-mercaptoacetate treatments induced both a dramatic increase (> 15x) of
the hepatic pyruvate level and a significant reduction (-40%) of the
blood glucose level (Sabouraultet al., 1979; reliability 2). The
increase in hepatic pyruvate level could result from a direct/indirect
inhibition of the mitochondrial utilization of pyruvate by
Indeed, it has been shown, using rat hepatic
mitochondria, that mercaptoacetate could be a substrate for acetyl-CoA
synthase, following an ATP-dependent activation, and that the resulting
compound, 2-mercaptoacetyl-CoA could inhibitnon-specifically thefatty
(long-chaingeneralandshort-chainacyl-CoAdehydrogenases) as well as the
branched-chain acyl-CoA dehydrogenase, namely isovaleryl-CoA (Bauchéet
al., 1982 and Bauchéet al., 1983; Sabbaghet al.,
Mercaptoacetate injected parenterally or
administered by gavage, significantly depressed hepatic succinoxidase
(SO) in rats, mice and rabbits, the male displaying a higher sensitivity
than the adult female.In vitro, mercaptoacetate was without
affect on cytochrome oxidase and diaphorase activities but depressed
NADH cytochrome-c-reductase activity.In vivo, mercaptoacetatewas
without action on the SO activity in spleen and brain but was inhibited
in liver and kidneys of male rats. The activities of the hepatic
xanthine oxidase, D-amino acid oxidase, malic oxidase, LDH and alcohol
deshydrogenase as well as the activities of the renal LDH and alcohol
deshydrogenase were not affected. The feeding of diets supplemented with
excessive amounts of amino acids prior to the injection of
mercaptoacetate, protected against the action of the thiol(Bakshy and
Gershbein, 1971 and Bakshy and Gershbein, 1973).
Effects of mercaptoacetate on food
The effect of mercaptoacetate on food
consumption seems to depend on the age, the strain, the nutritional
status and on the nature of the dietary fat.
Several experiments have shown that
mercaptoacetate increased the food intake in medium- or high-fat fed
animals but not in low-fat fed animals (Scharrer and Langhans, 1986).
This increase was essentially due to the reduced interval between meals
rather than the increase of the meals size or duration(Langhans and
Scharrer, 1987). The inhibition exerted by mercaptoacetate on the
β-oxidation of the fatty acids was considered to be the earliest
metabolic signal modifying independent ingestion in rats (increase of
the plasma free fatty acids, decrease of plasma β-hydroxybutyrate
confirmed the inhibition). A long-term feeding-inhibitory effect could
also be observed after mercaptoacetate administrations, probably
mediated by a different mechanism than its feeding-stimulatory effect
(Brandtet al., 2006).
Several hypothesis were issued to explain the
control of the food intake by the β-oxidation:
decrease in reduced cofactors (Nordmann and Nordmann, 1971; Scharrer and
Langhans, 1986) increases the food intake.
inhibition of the β-oxidation decreased the membrane potential in liver
cell, which modulate the afferent vagal activity, stimulating the food
intake (Boutellieret al., 1999). Mercaptoacetate-induced enhanced
feeding in rats given fat-enriched diet does not depend on a stronger
hepatic and/or celiac vagal afferent response than rats given a low-fat
diet (Randichet al., 2002). In addition, the release of ketone
bodies could independently act on the afferent vagal activity.
NMDA receptors and the neurotransmitter glutamate may be involved in
processing these mecanoreceptive signals (Duvaet al., 2005).
results suggest that mercaptoacetate elicits a feeding inhibitory effect
in fasted rats, which could be due to an increased β-adrenergic
activity. Hypothermia, increased plasma free fatty acids levels and
eventually disturbances in glucose metabolism may have contributed
(Brandtet al., 2006).
deprivation does not contribute to feeding elicited by
mercaptoacetate-induced inhibition of fatty acid oxidation in rats fed a
carbohydrate-free, high-fat diet (Del Preteet al., 2001).
performed on food intake in developing rats (Switherset al.,
2000, Switherset al., 2001), in adequation with effects observed
in adult rats, show that the action of mercaptoacetate, by blockade of
fatty acid oxidation, stimulates independent ingestion and not suckling
or water intake. This stimulation does not work on younger animals,
9-weeks aged old or lower. This is probably due to a compensatory system
present at this period of development. In addition, mercaptoacetate has
a short-term action (shorter than to the duration of β-oxidation
inhibition) probably antagonized later by the disturbances of metabolite
homeostasis resulting from the impairment of fatty acid oxidation. At
high dose-levels of mercaptoacetate, inhibition of the food intake and
gastric emptying were observed.
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