Peroxynitrite flux-mediated LDL oxidation is inhibited by manganese porphyrins in the presence of uric acid.
We have studied the role of three Mn(III)porphyrins differing in charge, alkyl substituent length and reactivity, on LDL exposed to low fluxes of peroxynitrite (PN) in the presence of uric acid. Mn(III)porphyrins (5 microM, MnTE-2-PyP(5+), MnTnOct-2-PyP(5+), and MnTCPP(3-)) plus uric acid (300 microM) inhibited cholesteryl ester hydroperoxide formation, changes in REM as well as spared alpha- and gamma-tocopherol. MnTnOct-2-PyP(5+), the more lipophilic compound, was the most effective in protecting LDL lipids, while MnTCPP(3-) exerted the lesser protection. Mn(III)porphyrins react fast with PN ( approximately 10(5)-10(7) M(-1) s(-1)) to yield a O=Mn(IV) complex. The stoichiometry of uric acid consumption was approximately 1.7 moles per mol of PN, in agreement with reactions with both the O=Mn(IV) complex and nitrogen dioxide. A shift from an anti- to a pro-oxidant action of the Mn(III)porphyrin was observed after uric acid was significantly consumed, supporting competition reactions between LDL targets and uric acid for the O=Mn(IV) complex. Overall, the data is consistent with the catalytic reduction of PN in a cycle that involves a one electron oxidation of Mn(III) to Mn(IV) by PN followed by the reduction back to Mn(III) by uric acid. These antioxidant effects should predominate under in vivo conditions having plasma uric acid concentration range between 150 and 500 microM.
Trostchansky
Andrés
A
Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Ferrer-Sueta
Gerardo
G
Batthyány
Carlos
C
Botti
Horacio
H
Batinić-Haberle
Ines
I
Radi
Rafael
R
Rubbo
Homero
H
D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry*; D008345:Manganese / Q000378:metabolism*; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009585:Nitrogen Dioxide / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D014527:Uric Acid / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000378:metabolism; D024504:gamma-Tocopherol / Q000378:metabolism
D008077:Lipoproteins, LDL; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; C027155:manganese(III) porphyrin; D014527:Uric Acid; D008345:Manganese; D024504:gamma-Tocopherol; D006861:Hydrogen Peroxide; D024502:alpha-Tocopherol; D009585:Nitrogen Dioxide