Another worrying ALA rat study is set out below. Since Homocysteine = bad; S-adenosylmethionine (SAM) = good, as a result of this paper it might pay dividends for life extensionists to consider whether or not it is worth dropping ALA supplementation levels somewhat and increasing SAM supplementation.
Here is the Extract
Free Radic Biol Med. 2009 Oct 15;47(8):1147-53. Epub 2009 Jul 17.
Alpha-lipoic acid induces elevated S-adenosylhomocysteine and depletes
S-adenosylmethionine.
Stabler SP, Sekhar J, Allen RH, O'Neill HC, White CW.
Department of Medicine and Division of Hematology, University of
Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Sally.Stabler@ucdenver.edu
Lipoic acid is a disulfhydryl-containing compound used in clinical
medicine and in experimental models as an antioxidant. We developed a
stable isotope dilution capillary gas chromatography/mass spectrometry
assay for lipoic acid. We assayed a panel of the metabolites of
transmethylation and transsulfuration 30 min after injecting 100 mg/kg
lipoic acid in a rat model. Lipoic acid values rose 1000-fold in serum
and 10-fold in liver. A methylated metabolite of lipoic acid was also
detected but not quantitated. Lipoic acid injection caused a massive
increase in serum S-adenosylhomocysteine and marked depletion of liver
S-adenosylmethionine. Serum total cysteine was depleted but liver
cysteine and glutathione were maintained. Serum total homocysteine
doubled, with increases also in cystathionine, N,N-dimethylglycine,
and alpha-aminobutyric acid. In contrast, after injection of
2-mercaptoethane sulfonic acid, serum total cysteine and homocysteine
were markedly depleted and there were no effects on serum
S-adenosylmethionine or S-adenosylhomocysteine. We conclude that large
doses of lipoic acid displace sulfhydryls from binding sites,
resulting in depletion of serum cysteine, but also pose a methylation
burden with severe depletion of liver S-adenosylmethionine and massive
release of S-adenosylhomocysteine. These changes may have previously
unrecognized deleterious effects that should be investigated in both
human disease and experimental models.
PMID: 19616616
From the Discussion section of the full paper:
"Commonly used doses of LA in human disease range from 600 to 1800 mg/day [1],
which for a 70-kg person will range from roughly 9 to 26 mg/kg, thus
4- to 10-fold less than in our rat model. However, at the higher doses
it is likely that LA might pose a methylation burden and human subjects
should be tested for changes in transmethylation and transsulfuration
metabolites. A recent report suggests that an improved formulation of
R-(+)-LA has significantly higher bioavailability and, thus, might be
expected to have more effect on methylation status [38]. Placebo-controlled
trials in diabetic neuropathy have shown a clear benefit of LA with
few demonstrated side effects [1]. Fortunately, there is not a dose
response, with lower doses equally effective, which would probably
have less potential to cause hyperhomocysteinemia. In Parkinson
disease treatment with L-dopa, the hyperhomocysteinemia presumptively
attributed to the methylation burden has been correlated with vascular
disease [35]. Therefore some concern may be warranted if large doses
of LA are used in human medicine. An interesting difference in LA dose
toxicity has been described in cats compared to humans and dogs, which
could be investigated for methylation defects [39]. LA is being
investigated in cell models as a cancer chemotherapeutic agent because
high concentrations in the medium (100 umol/L-5 mmol/L) have been
reported to induce apoptosis in a variety of cell lines [40], [41],
[42] and [43]. The impact of probable SAM depletion and SAH-induced
transmethylation inhibition should be investigated in these systems.
"In summary, we have demonstrated that a common experimental dose of
LA causes massive depletion of liver SAM, elevation of serum SAH, and
increased tHcys in rats. Similar depletion of serum cysteine with
MESNA was not accompanied by changes in SAM and SAH, suggesting that
the former effects are due to various aspects of LA metabolism/
catabolism. Further studies in humans may be interesting."
Edited by hamishm00, 06 October 2009 - 07:05 PM.
