Abstract
Flavonoids are a class of dietary phytochemicals that modulate various biological activities. The effects of flavone and five hydroxylated derivatives on the methoxyresorufinO-demethylase activity catalyzed by cDNA-expressed human cytochromes P450 (CYP)1A1 and 1A2 were examined. Flavone was a less potent inhibitor of CYP1A1 (IC50 = 0.14 μM) than CYP1A2 (IC50 = 0.066 μM). Four hydroxylated flavone derivatives (3-hydroxy-, 5-hydroxy-, 7-hydroxy-, and 3,7-dihydroxyflavone) were also potent inhibitors of CYP1A1 (IC50 < 0.1 μM) and CYP1A2 (IC50 < 0.3 μM). For CYP1A1, 7-hydroxyflavone exhibited a competitive mode of inhibition, with aKi value of 0.015 μM and 6-fold selectivity for CYP1A1 over CYP1A2. 3,5,7-Trihydroxyflavone (galangin) showed the highest potency toward CYP1A2. The inhibition by galangin of the methoxyresorufin O-demethylase activity of CYP1A2 was mixed-type, with a Ki value of 0.008 μM. Galangin showed 5-fold selectivity in its inhibition of CYP1A2 over CYP1A1. The results indicate that some flavonoids have high potencies and selectivities for inhibition of CYP1A isozymes. This may have important implications for cancer prevention, as well as other pharmacological and toxicological effects of these compounds.
Footnotes
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Send reprint requests to: Robert E. Vestal, M.D., Research Service (151), VA Medical Center, 500 West Fort Street, Boise, ID 83702.
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This work was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service), the National Institutes of Health (National Cancer Institute), and the Mountain States Medical Research Institute.
- Abbreviations used are::
- P450 or CYP
- cytochrome P450
- MROD
- 7-methoxyresorufin O-demethylase
- G-6-P
- glucose-6-phosphate
- G-6-PD
- glucose-6-phosphate dehydrogenase
- Received February 16, 1998.
- Accepted June 9, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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