Glyoxals are reactive alpha-oxoaldehydes that are formed endogenously from
sugars, the levels of which are increased in various pathological conditions associated with hyperglycaemia and
thiamine deficiency. However, the molecular cytotoxic mechanisms of
glyoxal are not known. Results presented here and in the other studies cited provide a glimpse into the cytotoxicity mechanisms involved and their pathological implications. We found that
glyoxal (10 microM) markedly increased the susceptibility of hepatocyte
glutathione (GSH) to oxidation by
hydrogen peroxide (H(2)O(2)) and markedly increased cytotoxicity by compromising the cellular
antioxidant enzyme system. At higher concentrations,
glyoxal was cytotoxic towards hepatocytes, which can be attributed to GSH depletion, oxidative stress and mitochondrial toxicity.
Aminoguanidine or
penicillamine protected the hepatocytes.
Glyoxal cytotoxicity was prevented by increasing
glyoxal metabolism with
thiamine or
NAD(P)H generators, and was increased in GSH- or
thiamine-deficient hepatocytes. It was also found that feeding rats reduced
thiamine levels in a diet high in
simple sugars increased the number of
aberrant crypt foci/colon in the absence of clinical evidence of
beriberi. This was associated with decreased plasma
thiamine and low erythrocyte
transketolase activity. Western diets, which are frequently poor in
thiamine and high in
sugars, could result in increased levels of endogenous glyoxals, which in turn may lead to a predisposition to AGE (
advanced glycation end-product)-related pathologies and neoplastic conditions.