Hepatocyte inflammation model for cytotoxicity research: fructose or glycolaldehyde as a source of endogenous toxins.
Insulin resistance and hepatotoxicity induced in high fructose fed rats may involve fructose derived endogenous toxins formed by inflammation. Thus fructose was seventy-fold more toxic if hepatocytes were exposed to non-toxic levels of hydrogen peroxide (H(2)O(2)) released by inflammatory cells. This was prevented by iron (Fe) chelators, hydroxyl radical scavengers, and increased by Fe, copper (Cu) or catalase inhibition. Fructose or glyceraldehyde/dihydroxyacetone metabolites were oxidized by Fenton radicals to glyoxal. Glyoxal (15 microM) cytotoxicity was increased about 200-fold by H(2)O(2). Glycolaldehyde was enzymically formed from glyceraldehyde, the fructokinase/aldolase B product of fructose. Glycolaldehyde cytotoxicity was increased 20-fold by H(2)O(2). The oxidative stress cytotoxicity induced was attributed to the Fenton oxidation of glycolaldehyde forming glycolaldehyde radicals and glyoxal, since cytotoxicity was prevented by aminoguanidine (glyoxal trap) or Fenton inhibitors. Glyoxal was also the Fenton product responsible for glycolaldehyde protein carbonylation as carbonylation was prevented by aminoguanidine or Fenton inhibitors.
Feng
C Y
CY
Department of Pharmacology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Wong
S
S
Dong
Q
Q
Bruce
J
J
Mehta
R
R
Bruce
W R
WR
O'Brien
P J
PJ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000378:metabolism*; D006037:Glyoxal / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012106:Research; D013997:Time Factors; D014118:Toxins, Biological / Q000378:metabolism*
D000975:Antioxidants; D014118:Toxins, Biological; D005632:Fructose; D006037:Glyoxal; D006861:Hydrogen Peroxide; D000079:Acetaldehyde; C010972:glycolaldehyde