Differential mechanisms of cytochrome P450 inhibition and activation by α-naphthoflavone

Aditya P. Koley, Jeroen T.M. Buters, Richard C. Robinson, Allen Markowitz, Fred K. Friedman

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

The anticarcinogenicity of some flavonoids has been attributed to modulation of the cytochrome P450 enzymes, which metabolize procarcinogens to their activated forms. However, the mechanism by which flavonoids inhibit some P450-mediated activities while activating others is a longstanding, intriguing question. We employed flash photolysis to measure carbon monoxide binding to P450 as a rapid kinetic technique to probe the interaction of the prototype flavonoid α-naphthoflavone with human cytochrome P450s 1A1 and 3A4, whose benzo[a]pyrene hydroxylation activities are respectively inhibited and stimulated by this compound. This flavonoid inhibited P450 1A1 binding to benzo[a]pyrene via a classical competitive mechanism. In contrast, α- naphthoflavone stimulated P450 3A4 by selectively binding and activating an otherwise inactive subpopulation of this P450 and promoting benzo-[a]pyrene binding to the latter. These data indicate that flavonoids enhance activity by increasing the pool of active P450 molecules within this P450 macrosystem. Activators in other biological systems may similarly exert their effect by expanding the population of active receptor molecules.

Original languageEnglish
Pages (from-to)3149-3152
Number of pages4
JournalJournal of Biological Chemistry
Volume272
Issue number6
DOIs
StatePublished - 1997
Externally publishedYes

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