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Role of the hepatic xanthine oxidase in thyroid dysfunction: effect of
thyroid hormones in oxidative stress in rat liver.
Huh K; Kwon TH; Kim JS; Park JM
Department of Pharmacology, College of Pharmacy, Yeungnam University,
Arch Pharm Res, 21(3):236-40 1998 Jun
- Glutathione (GSH) is a tripeptide formed from glutamic acid, cysteine, and
glycine. Combined with vitamin E and selenium, glutathione forms glutathione
peroxidase (GPx) which is one of the key antioxidants that protects the body
and is critical for protection of the thyroid gland from oxidation damage.
- Low levels of glutathione (along with low levels of vitamin E and
selenium) may be a factor in the genesis of thyroid disease. Excessive
intake of sugars and starches may reduce glutathione and thereby damage the
The effect of thyroid hormones on the hepatic xanthine oxidase activity was
studied in rats after the intraperitoneal injections of comthyroid (triiodotyronine:thyroxine
= 1:4) at 0.3 mg/kg for 3 consecutive days. The aim of this study was to
understand the precise mechanism of hyperthyroidism induced by oxidative stress.
The concentration of lipid peroxides determined indirectly by the measurement of
thiobarbituric acid reactants was increased in comthyroid treated rats. The
hepatic glutathione content was decreased in comthyroid injected
rat compared to the euthyroid state. It was also observed that the increment of
xanthine oxidase activity has a profound role in oxygen radicals generation
system in comthyroid treated rat. These findings suggest that the enhanced
xanthine oxidase activity and depleting glutathione content in
comthyroid treated rats result in pathophysiological oxidative stress including
an increment of hepatic lipid peroxidation.
The effect of methimazole on the oxidant and antioxidant system in patients
Ademo¨glu E; G¨okku¸su C; Yarman S; Azizlerli H
Department of Biochemistry, Istanbul Faculty of Medicine, University of
Pharmacol Res, 38(2):93-6 1998 Aug
The present study was designed to evaluate the changes in the plasma lipid
peroxidation and antioxidant system in 15 adult volunteer patients in
hyperthyroid and euthyroid states. In these patients, plasma concentrations of
lipid peroxides were decreased and, ascorbic acid and vitamin E levels were
significantly increased in euthyroid status in comparison to hyperthyroid
status. A significant increase in the plasma GPx activity (P < 0.01) and a
decrease in GST (P < 0.001) was observed after euthyroidism was sustained
with methimazole therapy. In conclusion, hyperthyroidism tends to enhance
lipid peroxide content and an increase in GST and decreases in GPx, vitamin E
and ascorbic acid levels accompany to this change in the plasma. The
achievement of euthyroidism led an improvement in these parameters.
The effect of iron supplementation on GSH levels, GSH-Px, and SOD activities
of erythrocytes in L-thyroxine administration.
Seymen O; Seven A; Candan G; Yigit G; Hatemi S; Hatemi H
Department of Physiology, Cerrahpasa Medical Faculty, Istanbul University,
Acta Med Okayama, 51(3):129-33 1997 Jun
Our aim was to study the effect of iron supplementation on the following
aspects of erythrocyte metabolism in experimental hyperthyroidism: glutathione
(GSH) levels, glutathione peroxidase (GSH-Px), and superoxide
dismutase (SOD) activities. Hyperthyroidism induced by L-thyroxine
administrations significantly raised erythrocyte GSH, GSH-Px and SOD levels of
the rats (P < 0.001). Likewise, we observed that iron supplementation
induced significant rises in erythrocyte GSH, GSH-Px and SOD levels (P <
0.001) as compared with the control group. The erythrocyte GSH, GSH-Px and SOD
levels of hyperthyroidism-induced iron-supplemented animals were significantly
higher when compared with either the iron-supplemented group (P < 0.001) or
the only L-thyroxine-administered hyperthyroid group (P < 0.001, P <
0.05, P < 0.01, respectively). The results of this study show that
L-thyroxine administration and/or iron supplementation increases GSH, GSH-Px
and SOD levels of erythrocytes.
- This study shows that iron supplementation can increase the production of
glutathione and glutathione peroxidase.
Copper-glutathione complexes under physiological conditions: structures in
solution different from the solid state coordination.
Pederson JZ; Steink¨uhler C; Weser U; Rotilio G
Department of Biology, University of Rome Tor Vergata, Italy.
Biometals, 9(1):3-9 1996 Jan
The physiologically important copper complexes of oxidized glutathione
have been examined by electron spin resonance (ESR) spectroscopy in aqueous
solution at neutral pH. Low temperature measurements show that the Cu(II)
binding site in oxidized glutathione has the same ligand arrangement as in
copper complexes of S-methylglutathione, glutamine, glutamate
and glycine. The site is composed of the amino nitrogens and the carboxyl
oxygens of two gamma-glutamyl residues; there is no interaction with amide
nitrogens, the sulphur bond or the glycyl carboxyl groups. At high metal to
ligand ratios a binuclear species exists, in which each Cu(II) binds only to
one gamma-glutamyl residue. The previously reported forbidden transition
detected at g = 4 is due to non-specific aggregation and not to spin
coupling of intramolecular sites. Liquid solution ESR spectra show the Cu(II)-glutathione
complex has a lower mobility than the corresponding
Cu(II)-S-methylglutathione species. From the degree of spectral anisotropy
the complex with glutathione is calculated to exist as a dimer. These
results demonstrate that the physiologically relevant complex between copper
and oxidized glutathione in solution is completely different from the known
solid state structure determined by crystallography.
Role of cytosolic copper, metallothionein and glutathione in
copper toxicity in rat hepatoma tissue culture cells.
Steinebach OM; Wolterbeek HT
Department of Radiochemistry, Delft University of Technology, The
Toxicology, 92(1-3):75-90 1994 Sep 6
Effects of metallothionein (MT) synthesis inhibiting compounds (actinomycin
D, cycloheximide), MT synthesis stimulating compounds (dexamethasone,
dibu-cAMP) and interfering metals (Cd, Zn) on copper
accumulation were investigated in rat hepatoma tissue culture cells. Copper-metallothionein
(Cu-MT) and MT-associated copper levels were determined to
find a possible correlation between cytosolic copper
concentrations and MT as a Cu-detoxifying protein. Further, intracellular
non-MT associated copper levels and levels of GSH and SOD were
determined. Cell viability was tested under all experimental conditions by
measuring LDH-release, K+ uptake and total cell protein. Administration of
dexamethasone and dibu-cAMP showed no effect on MT levels (compared with
controls), and only a marginal effect on 64Cu and total Cu accumulation.
Administration of actinomycin D resulted in increased copper
accumulation in the particulate fraction, possibly due to inhibition of copper
secretion processes and/or protein synthesis. Presence of zinc had no effect
on MT levels nor on total Cu and 64Cu levels, in contrast with cadmium which
drastically enhanced copper accumulation and MT levels in the
cells. Cu/MT ratios varied from 1.0 +/- 0.3 to 3.3 +/- 1.2, which is far
below the assumed maximum molar ratio of 8-12 mol Cu per mol MT. SOD levels
appeared to be enhanced up to 2- or 3-fold in the presence of Cd2+, relative
to control values. The role of GSH as Cu-intermediate in intracellular Cu
distribution plus its role in copper defence mechanism(s) was
tested by application of BSO, an inhibitor of GSH synthesis. It was found
that BSO had no effect on intracellular MT level; it was found however that
MT-bound copper levels were markedly decreased. The results
presented support a model for copper metabolism in hepatoma
tissue culture (HTC) cells, where Cu(I) is complexed by GSH immediately
after entering the cell. GSH is capable of transferring copper
to MT where it is stored. Depletion of GSH (by administration of Cd2+,
actinomycin D, cycloheximide) almost instantaneously results in enhanced
cellular toxicity. When also MT is depleted (by actinomycin D) non-MT
associated, 'free' cytosolic Cu2+ is elevated, and HTC cells rapidly loose
their resistance to copper toxicity, as also reflected in loss
of cell viability (LDH, K+ and total cell protein).
The role of glutathione in copper metabolism and toxicity.
Freedman JH; Ciriolo MR; Peisach J
Institute for Structural and Functional Studies, University City Science
Center, Philadelphia, Pennsylvania 19140.
J Biol Chem, 264(10):5598-605 1989 Apr 5
Cellular copper metabolism and the mechanism of resistance to copper
toxicity were investigated using a wild type hepatoma cell line (HAC) and a
copper-resistant cell line (HAC600) that accumulates copper and has a highly
elevated level of metallothionein (MT). Of the enzymes involved in reactive
oxygen metabolism, only glutathionine peroxidase was elevated (3-4-fold) in
resistant cells, suggestive of an increase in the cellular flux of hydrogen
peroxide. A majority of the cytoplasmic copper (greater than 60%) was
isolated from both cell lines as a GSH complex. Kinetic studies of 67Cu
uptake showed that GSH bound 67Cu before the metal was complexed by MT.
Depletion of cellular GSH with buthionine sulfoximine inhibited the
incorporation of 67Cu into MT by greater than 50%. These results support a
model of copper metabolism in which the metal is complexed by GSH soon after
entering the cell. The complexed metal is then transferred to MT where it is
stored. This study also indicates that resistance to metal toxicity in
copper-resistant hepatoma cells is due to increases in both cellular GSH and
MT. Furthermore, it is suggested that elevated levels of GSH peroxidase
allows cells to more efficiently accommodate an increased cellular hydrogen
peroxide flux that may occur as a consequence of elevated levels of
J Endocrinol Invest 1993 Apr;16(4):265-70
Acute iodine ingestion increases intrathyroidal glutathione.
Department of Medicine, University of Maryland Medical School, Baltimore.
In genetically predisposed individuals, autoimmune lymphocytic thyroiditis
(LT) is potentiated by excess dietary iodine (I). There have been data which
suggest that oxidative stress may have a role in iodine-induced LT. These in
vivo studies were undertaken to examine the effect of iodine on intrathyroidal
levels of the potent antioxidant glutathione (GSH) and see if the thyroids of
LT-prone BB/Wor rats have aberrant GSH responses after iodine-loading.
LT-prone BB/Wor, non LT-prone BB/Wor and Wistar rats were randomized to
receive either 0.05% I (as Nal) or tap water. Thyroid and liver homogenates
were assayed individually for GSH. Following the administration of 0.05%
iodine water overnight, all of the animals demonstrated a rise in
intrathyroidal GSH regardless of LT-proneness. To determine whether this was a
dose-dependent response, Wis rats were randomized to receive tap, 0.0125%,
0.025%, 0.05%, or 0.075% I, overnight. Intrathyroidal GSH levels rose with
increasing iodine concentrations peaking at 0.025% I. Hepatic GSH levels were
unaltered by iodine treatment. Ten days of 0.05% I water did not result in any
difference between the GSH levels of thyroids from treated and control rats.
Frozen sections of the thyroids and livers from iodine-treated rats were
compared to tap-water controls after staining with Mercury Orange for GSH and
Schiff's reagent for evidence of lipid peroxidation. Iodine-treated thyroids
had an apparent shift of GSH staining from the apical border to the cytoplasm.
However, there was no Schiff's staining indicative of lipid peroxidation in
the iodine-treated thyroids.
PMID: 7685786, UI: 93294146
- Hepatic glutathione biosynthetic capacity in hyperthyroid
- Fern´andez V; Videla LA
- Departamento de Bioqu´imica, Facultad de Medicina, Universidad de Chile,
- Toxicol Lett, 89(2):85-9 1996 Dec 16
The influence of hyperthyroidism on the capacity of the liver to synthesize glutathione
(GSH) was evaluated as a possible mechanism of depletion of the tripeptide. For
this purpose, the effect of daily doses of 0.1 mg 3, 3',5-tri-iodothyronine
(T3)/kg for 3 consecutive days on hepatic GSH biosynthetic capacity was assessed
by a combined assay measuring gamma-glutamylcysteinyl synthase and GSH synthase
simultaneously. T3 treatment induced a significant 56% depletion of liver GSH in
parallel with an increase in the rate of GSH synthesis, the latter effect being
completely abolished by L-buthionine sulfoximine. According to these data, the
fractional rate of hepatic GSH turnover exhibited a 3.2-fold enhancement in
hyperthyroid rats compared to control animals. It is concluded that the enhanced
GSH utilization in the liver of hyperthyroid rats previously observed [Fern´andez
et al., Endocrinology 129, 85-91, 1991], is accompanied by an increment in GSH
synthesis that is insufficient to sustain the basal levels of the tripeptide
observed in euthyroid animals, thus establishing a low steady-state content of
GSH in the tissue.
Glucose may induce cell death through a free radical-mediated mechanism.
Donnini D; Zambito AM; Perrella G; Ambesi-Impiombato FS; Curcio F
Dipartimento di Patologia e Medicina Sperimentale e Clinica, University of
Udine Medical School, Italy.
Biochem Biophys Res Commun, 219(2):412-7 1996 Feb 15
It has been reported that glucose may autooxidize generating free radicals
which have been hypothesized to induce important cellular abnormalities. To
investigate the cell damage induced by glucose-dependent oxidative stress, the
FRTL5 cell strain was incubated in 10 or 20 mM glucose, either alone or in the
presence of buthionine-sulfoximine, a transition state inhibitor
that blocks glutathione synthesis. We found indeed that buthionine-sulfoximine
greatly inhibited glutathione production and increased malondialdehyde (a marker
of oxidative cell damage) levels, especially in 20mM glucose. We also found
that, when glutathione production was inhibited, 10mM glucose induced apoptosis
and 20 mM glucose induced necrosis. These data show that the glucose-dependent
cell damage is a function of glutathione production. They also show that such
glucose-dependent free radical production may be critical for determining cell
damage, even for small variations as the ones we tested (from 10 to 20 mM
Following is an article from Dr. Mercola's website,
mercola.com, which talks about how high blood sugar can decrease glutathione
and increase malonaldehyde, which can damage the thyroid and pancreas.
Lowering Blood Sugar Raises Glutathione
and Vitamin E Levels
In this study of patients with type 2 diabetes, blood
levels of two vital nutrients - glutathione and vitamin E - were found to
increase when glucose levels dropped and blood sugar became better controlled.
In addition, levels of both of these nutrients increased
even further in patients who received four weeks of vitamin E supplementation.
Although most people know about vitamin E, glutathione
is not quite so well-known. It is a peptide consisting of glutamic acid,
cysteine, and glycine. It serves as a critical co-enzyme for many reactions in
In addition to the increased glutathione and vitamin E
levels, levels of malonaldehyde, a naturally occurring possible carcinogen, were
reduced following the reduction of blood glucose levels. Malonaldehyde occurs as
a natural metabolic byproduct of prostaglandin synthesis and as an end product
of polyunsaturated lipid peroxidation. The CDC has reported that there was clear
evidence of carcinogenic activity in rats administered malonaldehyde,
particularly effecting the thyroid gland and pancreas.
Annals of Nutrition and Metabolism 2000;
COMMENT: Glutathione is one of the most essential
antioxidants. One can take supplements for it, but the only form that works is
the reduced form and this is very difficult to absorb orally. It is much more
cost effective to supplement with precursors or items like alpha lipoic acid
that regenerates glutathione. It also has the ability to regenerate other
antioxidants such as vitamins C and E. Red meat and organ meats are the best
sources of alpha lipoic acid. Glutamine is also a useful nutrient that improves
intestinal health and also serves as a direct precursor to glutathione, and some
investigators believe it to be the rate-limiting nutrient for glutathione
Some nutritional authorities recommend taking a form of
cysteine known as N-acetyl-cysteine (NAC), but I would advise against using this
supplement if you still have mercury amalgam fillings because it could interfere
with the detoxification of the mercury. Personally I consume 300 mg of alpha
lipoic acid and 5,000 mg of glutamine and 2,500 mg of vitamin C before I do my
seven-mile run as I believe it will maximize the glutathione production to
decrease the damage from the free radicals that I generate when I exercise.
Controlling the damage from free radicals is one of the keys to slowing down the