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TOXICOLOGY

Inhibition of Mitochondrial Hydrogen Peroxide Production by Lipophilic Metalloporphyrins

Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado (P.R.C., D.A.D., M.P.); and Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado (B.J.D.)

Many studies have established a role for oxidative stress and mitochondrial dysfunction as an important mechanism in the pathogenesis of neuronal disorders. Metalloporphyrins are a class of catalytic antioxidants that are capable of detoxifying a wide range of reactive oxygen species. The AEOL112 series of glyoxylate metalloporphyrins were designed with increased lipid solubility for better oral bioavailability and penetration of the blood-brain barrier. The goal of this study was to develop an in vitro assay using rat brain mitochondria to reliably detect endogenously released hydrogen peroxide (H₂O₂) and identify glyoxylate metalloporphyrins based on rank order of potency for removal of physiologically relevant H₂O₂. A polarographic method was established for the sensitive, accurate, and reproducible detection of low levels of H₂O₂. The assay identified several potent glyoxylate metalloporphyrins with H₂O₂ scavenging potencies (IC₅₀) in the nanomolar range. These results provide a simplified in vitro model system to detect physiologically generated mitochondrial H₂O₂ as a screening tool to predict the biological efficacy of potential therapeutic entities.

Address correspondence to: Dr. Manisha Patel, Department of Pharmaceutical Sciences, 4200 East Ninth Ave., School of Pharmacy, C238, Denver, CO 80262. E-mail: manisha.patel{at}uchsc.edu

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