Mitochondrial biotransformation of omega-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and omega-(1-methyl-1H-imidazol-2-ylthio)alkanoic acids: a prodrug strategy for targeting cytoprotective antioxidants to mitochondria.
Mitochondrial reactive oxygen species (ROS) generation and the attendant mitochondrial dysfunction are implicated in a range of disease states. The objective of the present studies was to test the hypothesis that the mitochondrial beta-oxidation pathway could be exploited to deliver and biotransform the prodrugs omega-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and omega-(1-methyl-1H-imidazol-2-ylthio)alkanoic acids to the corresponding phenolic antioxidants or methimazole. 3- and 5-(Phenoxy)alkanoic acids and methyl-substituted analogs were biotransformed to phenols; rates of biotransformation decreased markedly with methyl-group substitution on the phenoxy moiety. 2,6-Dimethylphenol formation from the analogs 3-([2,6-dimethylphenoxy]methylthio)propanoic acid and 3-(2,6-dimethylphenoxy)acrylic acid was greater than that observed with omega-(2,6-dimethylphenoxy)alkanoic acids. 3- and 5-(1-Methyl-1H-imidazol-2-ylthio)alkanoic acids were rapidly biotransformed to the antioxidant methimazole and conferred significant cytoprotection against hypoxia-reoxygenation injury in isolated cardiomyocytes. Both 3-(2,6-dimethylphenoxy)propanoic acid and 3-(2,6-dimethylphenoxy)acrylic acid also afforded cytoprotection against hypoxia-reoxygenation injury in isolated cardiomyocytes. These results demonstrate that mitochondrial beta-oxidation is a potentially useful delivery system for targeting antioxidants to mitochondria.
Mitochondrial Research and Innovation Group, Department of Anesthesiology, Rochester, NY 14642, USA.
Kurt S
KS
Roser
Paul S
PS
Brookes
Andrew P
AP
Wojtovich
Leif P
LP
Olson
Jalil
J
Shojaie
Richard L
RL
Parton
M W
MW
Anders
D000179:Acrylates / Q000378:metabolism*; D000473:Alkanes / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D019610:Cytoprotection / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D000179:Acrylates; D000473:Alkanes; D011355:Prodrugs; D017382:Reactive Oxygen Species; C036658:acrylic acid