Prooxidant and antioxidant activity of vitamin E analogues and troglitazone.
The order of antioxidant effectiveness of low concentrations of vitamin E analogues, in preventing cumene hydroperoxide-induced hepatocyte lipid peroxidation and cytotoxicity, was 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC) > troglitazone > Trolox C > alpha-tocopherol > gamma-tocopherol > delta-tocopherol. However, vitamin E analogues, including troglitazone at higher concentrations, induced microsomal lipid peroxidation when oxidized to phenoxyl radicals by peroxidase/H2O2. Ascorbate or GSH was also cooxidized, and GSH cooxidation by vitamin E analogue phenoxyl radicals was also accompanied by extensive oxygen uptake and oxygen activation. When oxidized by nontoxic concentrations of peroxidase/H2O2, vitamin E analogues except PMC also caused hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation. The prooxidant order of vitamin E analogues in catalyzing hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation was troglitazone > Trolox C > delta-tocopherol > gamma-tocopherol > alpha-tocopherol > PMC. A similar order of effectiveness was found for GSH cooxidation or microsomal lipid peroxidation but not for ascorbate cooxidation. Except for troglitazone, the toxic prooxidant activity of vitamin E analogues was therefore inversely proportional to their antioxidant activity. The high troglitazone prooxidant activity could be a contributing factor to its hepatotoxicity. We have also derived equations for three-parameter quantitative structure-activity relationships (QSARs), which described the correlation between antioxidant and prooxidant activity of vitamin E ananlogues and their lipophilicity (log P), ionization potential (E(HOMO)), and dipole moment.
Tafazoli
Shahrzad
S
Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 2S2, Canada.
Wright
James S
JS
O'Brien
Peter J
PJ
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival; D002474:Cell-Free System; D002839:Chromans / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide; D015227:Lipid Peroxidation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D009195:Peroxidase; D010636:Phenols / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000737:chemistry; D024505:Tocopherols / Q000737:chemistry; D000077288:Troglitazone; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
D000975:Antioxidants; D002839:Chromans; D016877:Oxidants; D010636:Phenols; D045162:Thiazolidinediones; D014810:Vitamin E; C042329:phenoxy radical; D006861:Hydrogen Peroxide; D009195:Peroxidase; D005978:Glutathione; D000077288:Troglitazone; D024505:Tocopherols; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid