Lipoic acid increases glutathione production
and enhances the effect of mercury in human cell lines.
Hultberg B, Andersson A, Isaksson A.
Department of Clinical Chemistry, Institute of Laboratory Medicine,
University Hospital Lund, S-22185 Lund, Sweden.
Toxicology. 2002 Jun 14;175(1-3):103-10.
Thiols are known to influence the metabolism
of glutathione. In a previous study (Toxicology 156 (2001) 93)
dithiothreitol (DTT) did not show any effect on intra- or extracellular
glutathione concentrations in HeLa cell cultures but increased
the effects of mercury ions on glutathione concentrations, whereas
monothiols such as N-acetylcysteine (NAC) or glutathione did not.
In the present study, we have investigated the effects of thiols
as well as the interaction between thiols and mercury ions in
cultures of both HeLa and hepatoma cells. Furthermore, we have
added alpha-lipoic acid (LA) to the previously used test panel
of thiols, since it is metabolised intracellularly to a dithiol
(dihydrolipoate). The present study shows that LA increased intra-
and extracellular concentrations of glutathione in both HeLa and
hepatoma cell cultures. In contrast to results for HeLa cells,
the presence of DTT increased the intracellular glutathione concentration
in hepatoma cells. No increase of glutathione concentrations was
observed in hepatoma cell cultures in the presence of the monothiols
(NAC, homocysteine or glutathione) tested, in agreement with previous
findings in HeLa cell cultures. The presence of dithiols, either
DTT or dihydrolipoate (the metabolite of LA), increased the effects
of mercury ions on glutathione concentrations in hepatoma cells,
whereas monothiols such as NAC or glutathione did not, in agreement
with previous findings in HeLa cells. Thus, metabolic effects
of mercury ions were observed in hepatoma cells as well as in
HeLa cells at a lower concentration than the supposed toxicity
threshold for mercury in blood.
Lipoic acid as a means of metabolic therapy
of open-angle glaucoma
Filina AA, Davydova NG, Endrikhovskii SN, Shamshinova AM.
Vestn Oftalmol. 1995 Oct-Dec;111(4):6-8.
A total of 45 patients (90 eyes) with stages
I and II open-angle glaucoma (OAG) were examined, 26 of these
were administered lipoic acid in a daily dose of 0.075 g for 2
months and 19 were given 0.15 g daily for 1 month. Control group
consisted of 31 patients with OAG who were administered only local
hypotensive therapy. Vision acuity and visual field were checked
up, tonometry, tonography, and campimetry carried out, and levels
of nonprotein SH-groups and activity of gamma-glutamyl transpeptidase
measured in the lacrimal fluid. Improvement of the biochemical
parameters, visual function, and of the coefficient of efficacy
of liquid discharge was more expressed in the patients administered
lipoic acid in a daily dose of 0.15 g. Color campimetry results
indicate improved sensitivity of the visual analyzer under the
effect of treatment. Improvement was attained in approximately
45-47.5% of examined eyes, and was more often seen in patients
with stage II OAG: in 57-58% eyes. The effect of lipoic acid may
be explained by its antioxidant properties and direct influence
on ocular tissue metabolism.
Differential effects of lipoic acid stereoisomers
on glucose metabolism in insulin-resistant skeletal muscle.
Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler
Department of Physiology, University of Arizona,
Tucson 85721-0093, USA.
The racemic mixture of the antioxidant alpha-lipoic acid (ALA)
enhances insulin-stimulated glucose metabolism in insulin-resistant
humans and animals. We determined the individual effects of the
pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism
in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia,
and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were
treated intraperitoneally acutely (100 mg/kg body wt for 1 h)
or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg
of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake],
glycogen synthesis, and glucose oxidation were determined in the
epitrochlearis muscles in the absence or presence of insulin (13.3
nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake
by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect.
Although chronic R-(+)-ALA treatment significantly reduced plasma
insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated
obese animals, S-(-)-ALA treatment further increased insulin (15%)
and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased
by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration
resulted in only a 29% improvement. Chronic R-(+)-ALA treatment
elicited a 26% increase in insulin-stimulated glycogen synthesis
and a 33% enhancement of insulin-stimulated glucose oxidation.
No significant increase in these parameters was observed after
S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was
unchanged after chronic R-(+)-ALA treatment but was reduced to
81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore,
chronic parenteral treatment with the antioxidant ALA enhances
insulin-stimulated glucose transport and non-oxidative and oxidative
glucose metabolism in insulin-resistant rat skeletal muscle, with
the R-(+) enantiomer being much more effective than the S-(-)
Alpha-lipoic acid in liver metabolism and
Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L,
Rihn BH. Department of Molecular and Cell Biology, University
of California, Berkeley 94720-3200, USA.
Free Radic Biol Med. 1998 Apr;24(6):1023-39.
R-alpha-Lipoic acid is found naturally
occurring as a prosthetic group in alpha-keto acid dehydrogenase
complexes of the mitochondria, and as such plays a fundamental
role in metabolism. Although this has been known for decades,
only recently has free supplemented alpha-lipoic acid been found
to affect cellular metabolic processes in vitro, as it has the
ability to alter the redox status of cells and interact with thiols
and other antioxidants. Therefore, it appears that this compound
has important therapeutic potential in conditions where oxidative
stress is involved. Early case studies with alpha-lipoic acid
were performed with little knowledge of the action of alpha-lipoic
acid at a cellular level, but with the rationale that because
the naturally occurring protein bound form of alpha-lipoic acid
has a pivotal role in metabolism, that supplementation may have
some beneficial effect. Such studies sought to evaluate the effect
of supplemented alpha-lipoic acid, using low doses, on lipid or
carbohydrate metabolism, but little or no effect was observed.
A common response in these trials was an increase in glucose uptake,
but increased plasma levels of pyruvate and lactate were also
observed, suggesting that an inhibitory effect on the pyruvate
dehydrogenase complex was occurring. During the same period, alpha-lipoic
acid was also used as a therapeutic agent in a number of conditions
relating to liver disease, including alcohol-induced damage, mushroom
poisoning, metal intoxification, and CCl4 poisoning. Alpha-Lipoic
acid supplementation was successful in the treatment for these
conditions in many cases. Experimental studies and clinical trials
in the last 5 years using high doses of alpha-lipoic acid (600
mg in humans) have provided new and consistent evidence for the
therapeutic role of antioxidant alpha-lipoic acid in the treatment
of insulin resistance and diabetic polyneuropathy. This new insight
should encourage clinicians to use alpha-lipoic acid in diseases
affecting liver in which oxidative stress is involved. Scientific