title: Fructose and carbonyl metabolites as endogenous toxins.
abstract: Dietary fructose consumption is one of the environmental factors contributing to the development of obesity and a fatty liver (hepatic steatosis). A two-hit hypothesis has been proposed for progression of hepatic steatosis to the more serious non-alcoholic steatosis (NASH), with the first hit being hepatic steatosis, and the second hit being inflammation and associated oxidative stress caused by reactive oxygen species (ROS) formation. As well, fructose-fed rats develop insulin resistance and serum levels of methylglyoxal, a glycolytic metabolite, are increased. Previously we reported that glyoxal-induced hepatocyte cytotoxicity could be attributed to mitochondrial toxicity as mitochondrial membrane potential was decreased and cytotoxicity was increased several orders of magnitude by low non-cytotoxic doses of H(2)O(2) (hepatocyte inflammation model). In this study, we have assessed the toxicity of fructose towards hepatocytes and investigated the molecular cytotoxic mechanisms involved. Fructose itself was only toxic at 1.5M, whereas 12 mM caused 50% cell death in 2h if the hepatocytes were exposed to a non-cytotoxic dose of H(2)O(2) continuously generated by glucose and glucose oxidase. The cytotoxic mechanism involved oxidative stress as ROS and H(2)O(2) formation preceded cytotoxicity, and cytotoxicity was prevented by radical scavengers, lipid antioxidants and ROS scavengers. It is proposed that the highly potent Fenton derived ROS catalyse the oxidation of fructose and particularly its carbonyl metabolites glycolaldehyde, dihydroxyacetone, glyceraldehyde. The carbon radicals and glyoxal formed compromise the cell's resistance to H(2)O(2).
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
authors.forename: O
authors.initials: O
authors.lastname: Lee
authors.forename: W R
authors.initials: WR
authors.lastname: Bruce
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
authors.forename: J
authors.initials: J
authors.lastname: Bruce
authors.forename: R
authors.initials: R
authors.lastname: Mehta
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D005459:Fluorides / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008670:Metals / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008670:Metals; D005632:Fructose; D005459:Fluorides