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Title
Hg(II)-induced renal cytotoxicity: in vitro and in vivo implications
for the bioenergetic and oxidative status of mitochondria.
Author
Santos AC; Uyemura SA; Santos NA; Mingatto FE; Curti C
Address
Department of Clinical, Toxicological and Bromatological Analysis,
School of Pharmaceutical Sciences, University of S~ao Paulo,
Ribeir~ao
Preto, Brasil.
Source
Mol Cell Biochem, 177(1-2):53-9 1997 Dec
Abstract
The effects of Hg(II) on bioenergetic and oxidative status of
rat renal
cortex mitochondria were evaluated both in vitro, and in vivo
1 and 24
h after treatment of animals with 5 mg HgCl2/kg i.p. The parameters
assessed were mitochondrial respiration, ATP synthesis and hydrolysis,
glutathione content, lipid peroxidation, protein oxidation, and
activity of antioxidant enzymes. At low concentration (5 microM)
and
during a short incubation time, Hg(II) uncoupled oxidative
phosphorylation while at slightly higher concentration or longer
incubation time the ion impaired the respiratory chain. The rate
of ATP
synthesis and the phosphorylation potential of mitochondria were
depressed, although inhibition of ATP synthesis did not exceed
50%. In
vivo, respiration and ATP synthesis were not affected 1 h
post-treatment, but were markedly depressed 24 h later. ATP hydrolysis
by submitochondrial particle FoF1-ATPase was inhibited (also
by no more
than 50%) both in vitro, and in vivo 1 and 24 h post-treatment.
Hg(II)
induced maximum ATPase inhibition at about 1 microM concentration
but
did not have a strong inhibitory effect in the presence of Triton
X-100. Oxidative stress was not observed in mitochondria 1 h
post-treatment. However, 24 h later Hg(II) reduced the GSH/GSSG
ratio
and increased mitochondrial lipid peroxidation and protein oxidation,
as well as inhibited GSH-peroxidase and GSSG-reductase activities.
These results suggest that the following sequence of events may
be
involved in Hg(II) toxicity in the kidney: (1) inhibition of
FoF1-ATPase, (2) uncoupling of oxidative phosphorylation, (3)
oxidative
stress-associated impairment of the respiratory chain, and (4)
inhibition of ATP synthesis.
Title
Role of oxidative stress and the glutathione system in loss of
dopamine
neurons due to impairment of energy metabolism.
Author
Zeevalk GD; Bernard LP; Nicklas WJ
Address
UMDNJ-Robert Wood Johnson Medical School, Department of Neurology,
Piscataway, New Jersey 08854, USA.
Source
J Neurochem, 70(4):1421-30 1998 Apr
Abstract
Alterations in the glutathione system and impairment in energy
metabolism have both been implicated in the loss of dopamine
neurons in
Parkinson's disease. This study examined the importance of cellular
glutathione and the involvement of oxidative stress in the loss
of
mesencephalic dopamine and GABA neurons due to inhibition of
energy
metabolism with malonate, the reversible, competitive inhibitor
of
succinate dehydrogenase. Consistent with previous findings, exposure
to
malonate for 24 h followed by 48 h of recovery caused a dose-dependent
loss of the dopamine population with little effect on the GABA
population. Toxicity was assessed by simultaneous measurement
of the
high-affinity uptake of [3H dopamine and [14C GABA. Total glutathione
content in rat mesencephalic cultures was decreased by 65% with
a 24-h
pretreatment with 10 microM buthionine sulfoxamine. This reduction
in
glutathione level greatly potentiated damage to both the dopamine
and
GABA populations and removed the differential susceptibility
between
the two populations in response to malonate. These findings point
to a
role for oxidative stress occurring during energy impairment
by
malonate. Consistent with this, several spin-trapping agents,
alpha-phenyl-tert-butyl nitrone and two cyclic nitrones, MDL
101,002
and MDL 102,832, completely prevented malonate-induced damage
to the
dopamine neurons in the absence of buthionine sulfoxamine. The
spin-trapping agents also completely prevented toxicity to both
the
dopamine and GABA populations when cultures were exposed to malonate
after pretreatment with buthionine sulfoxamine to reduce glutathione
levels. Counts of tyrosine hydroxylase-positive neurons verified
enhancement of cell loss by buthionine sulfoxamine plus malonate
and
protection against cell loss by the spin-trapping agents. NMDA
receptors have also been shown to play a role in malonate-induced
dopamine cell loss and are associated with the generation of
free
radicals. Consistent with this, toxicity to the dopamine neurons
due to
a 1-h exposure to 50 microM glutamate was attenuated by the nitrone
spin traps. These findings provide evidence for an oxidative
challenge
occurring during inhibition of energy metabolism by malonate
and show
that glutathione is an important neuroprotectant for midbrain
neurons
during situations when energy metabolism is impaired.
Title
Low plasma glutamine in combination with high glutamate levels
indicate
risk for loss of body cell mass in healthy individuals: the effect
of
N-acetyl-cysteine.
Author
Kinscherf R; Hack V; Fischbach T; Friedmann B; Weiss C; Edler
L; B
artsch P; Dr oge W
Address
Division of Immunochemistry' Deutsches Krebsforschungszentrum'
Heidelberg' Germany.
Source
J Mol Med, 74(7):393-400 1996 Jul
Abstract
Skeletal muscle catabolism' low plasma glutamine' and high venous
glutamate levels are common among patients with cancer or human
immunodeficiency virus infection. In addition' a high glycolytic
activity is commonly found in muscle tissue of cachectic cancer
patients' suggesting insufficient mitochondrial energy metabolism.
We
therefore investigated (a) whether an "an-aerobic physical
exercise"
program causes similar changes in plasma amino acid levels' and
(b)
whether low plasma glutamine or high glutamate levels are risk
factors
for loss of body cell mass (BCM) in healthy human subJects' i.e.'
in
the absence of a tumor or virus infection. Longitudinal measurements
from healthy subJects over longer periods suggest that the age-related
loss of BCM occur mainly during episodes with high venous glutamate
levels' indicative of decreased muscular transport activity for
glutamate. A significant increase in venous glutamate levels
from 25 to
about 40 microM was seen after a program of "anaerobic physical
exercise." This was associated with changes in T lymphocyte
numbers.
Under these conditions persons with low baseline levels of plasma
glutamine' arginine' and cystine levels also showed a loss of
BCM. This
loss of BCM was correlated not only with the amino acid levels
at
baseline examination' but also with an increase in plasma glutamine'
arginine' and cystine levels during the observation period' suggesting
that a loss of BCM in healthy individuals terminates itself by
adJusting these amino acids to higher levels that stabilize BCM.
To
test a possible regulatory role of cysteine in this context we
determined the effect of N-acetyl-cysteine on BCM in a group
of
subJects with relatively low glutamine levels. The placebo group
of
this study showed a loss of BCM and an increase in body fat'
suggesting
that body protein had been converted into other forms of chemical
energy. The decrease in mean BCM/body fat ratios was prevented
by
N-acetyl-cysteine' indicating that cysteine indeed plays a regulatory
role in the physiological control of BCM.
Title
Antioxidant activity of silybin in vivo during long-term iron
overload
in rats.
Author
Pietrangelo A; Borella F; Casalgrandi G; Montosi G; Ceccarelli
D;
Gallesi D; Giovannini F; Gasparetto A; Masini A
Address
Dipartimento di Medicina Interna' University of Modena' Italy.
Source
Gastroenterology, 109(6):1941-9 1995 Dec
Abstract
BACKGROUND & AIMS: Hepatic iron toxicity may be mediated
by free
radical species and lipid peroxidation of biological membranes.
The
antioxidant property of silybin' a main constituent of natural
flavonoids' was investigated in vivo during experimental iron
overload.
METHODS: Rats were fed a 2.5% carbonyl-iron diet and 100 mg.kg
body
wt-1.day-1 silybin for 4 months and were assayed for accumulation
of
hepatic lipid peroxidation by-products by immunocytochemistry'
mitochondrial energy-dependent functions' and mitochondrial
malondialdehyde content. RESULTS: Iron overload caused a dramatic
accumulation of malondialdehyde-protein adducts into iron-filled
periportal hepatocytes that was decreased appreciably by silybin
treatment. The same beneficial effect of silybin was found on
the
iron-induced accumulation of malondialdehyde in mitochondria.
As to the
liver functional efficiency' mitochondrial energy wasting and
tissue
adenosine triphosphate depletion induced by iron overload were
successfully counteracted by silybin. CONCLUSIONS: Oral administration
of silybin protects against iron-induced hepatic toxicity in
vivo. This
effect seems to be caused by the prominent antioxidant activity
of this
compound.
Title
Gradual and rapid weight loss: effects on nutrition and performance
in
male athletes.
Author
Fogelholm GM; Koskinen R; Laakso J; Rankinen T; Ruokonen I
Address
Department of Applied Chemistry and Microbiology' University
of
Helsinki' Finland.
Source
Med Sci Sports Exerc, 25(3):371-7 1993 Mar
Abstract
We studied seven male wrestlers and three Judo athletes (weight
55-93
kg) during two weight reductions. In the "gradual"
procedure (GP)' a
5.0 +/- 0.4% (mean +/- SEM) weight loss was achieved in 3 weeks
by
energy restriction. In the "rapid" procedure (RP)'
6.0 +/- 0.6% of body
weight was lost in 2.4 days by fluid and diet restriction and
forced
sweating' and followed by a 5-h "loading" (food and
drinks ad libitum).
The net weight loss after GP and loading was 2.7 +/- 0.5%. Protein
intakes (4-d food records) during GP and RP were 71 +/- 16 and
RP 56
+/- 17 g.d-1' respectively. Carbohydrate intakes were 239 +/-
56 (GP)
and 182 +/- 55 g.d-1 (RP). During GP and RP' mean thiamin' magnesium'
and zinc intakes were at or below the respective recommendation.
Thiamin' riboflavin' potassium' iron' and zinc status' assessed
from
blood chemistry' remained stable during both procedures. Changes
in
vitamin B6 indicator (E-ASTAC) and S-magnesium concentration
were
different (P < 0.01) between the procedures' suggesting negative
trends
during GP. Sprint (30-m run) and anaerobic (1-min Wingate test)
performance was similar throughout the study. Following GP' vertical
Jump height with extra load increased by 6-8% (P < 0.01).
Jumping
results were not affected by RP. Hence' < or = 5% loss in
body weight
by either method did not impair experienced athletes` performance.
Title
Nitric oxide-mediated mitochondrial damage: a potential neuroprotective
role for glutathione.
Author
Bola~nos JP; Heales SJ; Peuchen S; Barker JE; Land JM; Clark
JB
Address
Department of Neurochemistry' Institute of Neurology' London'
England.
Source
Free Radic Biol Med, 21(7):995-1001 1996
Abstract
In this study we have investigated the mechanisms leading to
mitochondrial damage in cultured neurons following sustained
exposure
to nitric oxide. Thus' the effects upon neuronal mitochondrial
respiratory chain complex activity and reduced glutathione
concentration following exposure to either the nitric oxide donor'
S-nitroso-N-acetylpenicillamine' or to nitric oxide releasing
astrocytes were assessed. Incubation with
S-nitroso-N-acetylpenicillamine (1 mM) for 24 h decreased neuronal
glutathione concentration by 57%' and this effect was accompanied
by a
marked decrease of complex I (43%)' complex II-III (63%)' and
complex
IV (41%) activities. Incubation of neurons with the glutathione
synthesis inhibitor' L-buthionine-[S'R -sulfoximine caused a
maJor
depletion of neuronal glutathione (93%)' an effect that was accompanied
by a marked loss of complex II-III (60%) and complex IV (41%)
activities' although complex I activity was only mildly decreased
(34%). In an attempt to approach a more physiological situation'
we
studied the effects upon glutathione status and mitochondrial
respiratory chain activity of neurons incubated in coculture
with
nitric oxide releasing astrocytes. Astrocytes were activated
by
incubation with lipopolysaccharide/interferon-gamma for 18 h'
thereby
inducing nitric oxide synthase and' hence' a continuous release
of
nitric oxide. Coincubation for 24 h of activated astrocytes with
neurons caused a limited loss of complex IV activity and had
no effect
on the activities of complexes I or II-III. However' neurons
exposed to
astrocytes had a 1.7-fold fold increase in glutathione concentration
compared to neurons cultured alone. Under these coculture conditions'
the neuronal ATP concentration was modestly reduced (14%). This
loss of
ATP was prevented by the nitric oxide synthase inhibitor'
NG-monomethyl-L-arginine. These results suggest that the neuronal
mitochondrial respiratory chain is damaged by sustained exposure
to
nitric oxide and that reduced glutathione may be an important
defence
against such damage.
Title
N-acetyl-p-benzoquinone imine-induced changes in the energy metabolism
in hepatocytes.
Author
Andersson BS; Rundgren M; Nelson SD; Harder S
Address
Department of Toxicology' Karolinska Institute' Stockholm' Sweden.
Source
Chem Biol Interact, 75(2):201-11 1990
Abstract
The effect of N-acetyl-p-benzoquinone imine (NAPQI)' a reactive
metabolite of acetaminophen' on the energy metabolism in isolated
hepatocytes was investigated. Incubation of cells with NAPQI
(400
microM) resulted in an immediate uptake into the mitochondria'
followed
by both reduction and glutathione conJugation of the quinone
imine.
These reactions were extremely rapid and were associated with
depletion
of the mitochondrial ATP content (greater than 80% depletion
after 1
min exposure). The loss of ATP was accompanied by increases in
ADP and
AMP' as well as NADP. No effect on mitochondrial NAD was observed
during this initial phase. Similar alterations were produced
by NAPQI
in the cytosolic compartment. Furthermore' incubation of hepatocytes
with NAPQI inhibited oxygen consumption by nearly 90% within
10 s. In
parallel to these biochemical changes' there was marked bleb
formation
on the surface of the hepatocytes' which was found to precede
cell
death (trypan blue uptake). In conclusion' our results demonstrate
that
during exposure of hepatocytes to NAPQI' dramatic changes in
cellular
energy metabolism occur. These biochemical alterations may be
caused by
a rapid decrease in mitochondrial function' and they may play
an
important role in the initiation of NAPQI-induced cytotoxicity.
Title
Mechanisms of myocardial protection by amino acids: facts and
hypotheses.
Author
Pisarenko OI
Address
Institute of Experimental Cardiology' Cardiology Research Centre'
Moscow' Russia.
Source
Clin Exp Pharmacol Physiol, 23(8):627-33 1996 Aug
Abstract
1. Positive inotropic effect of taurine and improvement of cardiac
performance of failing heart are mediated through the modulation
of
Ca2+ movement through the sarcolemma. 2. Cardioprotection with
glutamate and aspartate is related to enhanced anaerobic energy
formation in mitochondria coupled with succinate formation and'
probably' with the relieving of glycolytic flux. During reperfusion'
both amino acids replenish the malate-aspartate shuttle reactants'
thereby facilitating glucose oxidation. 3. Increased intracellular
concentrations of branched chain amino acids (leucine' valine
and
isoleusine) stimulate formation of acetyl-coenzyme (CoA) and
succinyl-CoA and' thus' recovery of oxidative metabolism. 4.
Methionine
and cysteine enhance force of contraction by N-methylation of
membrane
phospholipids of the sarcolemma and sarcoplasmic reticulum. Methionine
and' to a lesser extent' cysteine may reduce myocardial damage
by
oxygen radical species. 5. Histidine exerts antioxidant properties
as a
scavenger of singlet oxygen and OH radicals. High concentrations
of
histidine provide intracellular buffering to stimulate anaerobic
energy
formation. |
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