Toxicity of glyoxals--role of oxidative stress, metabolic detoxification and thiamine deficiency.
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.
Shangari
N
N
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2.
Bruce
W R
WR
Poon
R
R
O'Brien
P J
PJ
D000818:Animals; D006037:Glyoxal / Q000633:toxicity*; D006801:Humans; D008658:Inactivation, Metabolic; D018384:Oxidative Stress; D013832:Thiamine Deficiency / Q000378:metabolism*
D006037:Glyoxal