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ToxSci Advance Access published online on February 9, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi108
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 9, 2004
Accepted February 1, 2005

Systems Toxicology

A NOVEL CLASS OF CYTOCHROME P450 REDUCTASE REDOX CYCLERS: CATIONIC MANGANOPORPHYRINS

Brian J. Day 1* and Chirag Kariya 2

1 Department of Medicine, National Jewish Medical & Research Center, Denver, Colorado; Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado
2 Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado

* To whom correspondence should be addressed.
Brian J. Day, E-mail: dayb{at}njc.org


  Abstract

Manganese porphyrins are a potent class of catalytic antioxidants whose activity was recently shown to be partially dependent upon flavin-containing enzymes (Kachadourian et al. 2004). We tested whether manganese porphyrins could redox cycle with the flavin-containing enzyme, cytochrome P450 reductase, and whether this results in the inhibition of xenobiotic metabolism. The effect of manganese porphyrins on xenobiotic metabolism in rat and human liver microsomes was assessed spectrofluorometrically by following the O-dealkylation of benzyloxy- (BROD) and methoxyresorufin (MROD). Redox cycling of manganese porphyrins with human cytochrome P450 reductase was assessed both spectrophotometrically and polarographically by following the consumption of NADPH and oxygen, respectively. The tetrakis(N-pyridinium-2-yl) meso-substituted manganoporphyrin, MnTEPyP5+, and the tetrakis(1,3-dimethyl imidazolium-2-yl) meso-substituted manganoporphyrin, MnTDMIP5+, were 40 to 100 times more potent inhibitors of rat and human liver microsomal BROD metabolism than the tetrakis(1,3-diethyl imidazolium-2-yl) meso-substituted manganoporphyrin, MnTDEIP5+, or the tetrakis(4-benzoic acid) meso-substituted manganoporphyrin, MnTBAP. A similar pattern of inhibition was also seen in {beta}-naphthoflavone-induced rat liver microsomal MROD metabolism. This pattern of xenobiotic metabolism inhibition correlated with the compound's ability to redox cycle with cytochrome P450 reductase where MnTEPyP5+ was more potent than MnTDEIP5+. Furthermore, redox cycling of MnTEPyP5+ with cytochrome P450 reductase was inhibited by the flavin domain inhibitor diphenyleneiodonium. Small changes to the carbon chain length on the imidazolium side groups had a large effect on this activity. It is possible that interactions between manganoporphyrins and flavin-dependent oxidoreductases can account for both adverse and beneficial effects of the compounds.

Keywords: xenobiotic metabolism; catalytic antioxidants; oxidoreductase; human; rat.
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