title: Exploiting endobiotic metabolic pathways to target xenobiotic antioxidants to mitochondria.
abstract: Oxidative stress plays a role in a range of human disease entities. Hence, strategies to target antioxidants to mitochondria are an active area of investigation. Triphenylphosphonium cation-based antioxidants and SS-peptides have been described and show significant uptake by mitochondria and effectiveness in animal models of conditions linked to oxidative stress. We tested the hypothesis that the mitochondrial β-oxidation pathway could be exploited to activate the antioxidant phenolic and methimazole prodrugs. Most compounds studied underwent mitochondrial biotransformation to release their antioxidant moieties, and some were cytoprotective in a hypoxia-reoxygenation model in rat cardiomyocytes. These results demonstrate the feasibility of exploiting mitochondrial bioactivation reactions for targeted drug delivery.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA. mw_anders@urmc.rochester.edu
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001711:Biotransformation; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D053858:Metabolic Networks and Pathways; D008713:Methimazole / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010636:Phenols / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D010636:Phenols; D011355:Prodrugs; D015262:Xenobiotics; D008713:Methimazole
keywords: Antioxidants; Drug targeting; Mitochondria; Prodrugs; β-oxidation