Preventing cell death induced by carbonyl stress, oxidative stress or mitochondrial toxins with vitamin B anti-AGE agents.
Carbonyls generated by autoxidation of carbohydrates or lipid peroxidation have been implicated in advanced glycation end product (AGE) formation in tissues adversely affected by diabetes complications. Tissue AGE and associated pathology have been decreased by vitamin B(1)/B(6) in trials involving diabetic animal models. To understand the molecular cytoprotective mechanisms involved, the effects of B(1)/B(6) vitamers against cytotoxicity induced by AGE/advanced lipid end product (ALE) carbonyl precursors (glyoxal/acrolein) have been compared to cytotoxicity induced by oxidative stress (hydroperoxide) or mitochondrial toxins (cyanide/copper). Thiamin was found to be best at preventing cell death induced by carbonyl stress and mitochondrial toxins but not oxidative stress cell death suggesting that thiamin pyrophosphate restored pyruvate and alpha-ketoglutarate dehydrogenases inhibited by mitochondrial toxicity. However, B(6) vitamers were most effective at preventing oxidative stress or lipid peroxidation cytotoxicity suggesting that pyridoxal or pyridoxal phosphate were antioxidants and/or Fe/Cu chelators. A therapeutic vitamin cocktail could provide maximal prevention against carbonyl stress toxicity associated with diabetic complications.
Mehta
Rhea
R
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Shangari
Nandita
N
O'Brien
Peter J
PJ
D000171:Acrolein / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D019327:Copper Sulfate / Q000494:pharmacology; D003486:Cyanides / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006037:Glyoxal / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013831:Thiamine / Q000494:pharmacology; D025101:Vitamin B 6 / Q000494:pharmacology; D014803:Vitamin B Complex / Q000494:pharmacology*
D000447:Aldehydes; D003486:Cyanides; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D014803:Vitamin B Complex; D006037:Glyoxal; D000171:Acrolein; D025101:Vitamin B 6; D019327:Copper Sulfate; D013831:Thiamine