Selective inhibition of methoxyflavonoids on human CYP1B1 activity.

Abstract

Cytochrome P450 (CYP) 1B1 catalyzes 17beta-estradiol (E(2)) to predominantly carcinogenic 4-hydroxy-E(2), whereas CYP1A1 and 1A2 convert E(2) to non-carcinogenic 2-hydroxy-E(2). Hence, selective inhibition of CYP1B1 is recognized to be beneficial for the prevention of E(2) related breast cancer. In this study, we first evaluated the structure-property relationship of 18 major flavonoids on inhibiting enzymatic activity of CYP1A1, 1A2 and 1B1 by using an ethoxyresorufin O-deethylation assay. Flavones and flavonols indicated relatively strong inhibitory effects on CYP1s compared with flavanone that does not have the double bond between C-positions 2 and 3 on the C-ring. Flavonoids used in this study selectively inhibited CYP1B1 activity. In particular, methoxy types of flavones and flavonols such as chrysoeriol and isorhamnetin showed strong and selective inhibition against CYP1B1. To understand why selective inhibition was observed, we carried out a molecular docking analysis of these methoxyflavonoids with the 2-3 double bond and CYP1s. The results suggested that chrysoeriol and isorhamnetin fit well into the active site of CYP1B1, but do not fit into the active site of CYP1A2 and 1A1 because of steric collisions between the methoxy substituent of these methoxyflavonoids and Ser-122 in CYP1A1 and Thr-124 in CYP1A2. In conclusion, our results demonstrate: (1) strong inhibitory effects of flavonoids on CYP1 activities require the 2-3 double bond on the C-ring; (2) methoxyflavonoids with the 2-3 double bond had strong and selective inhibition against CYP1B1, suggesting chemopreventive flavonoids for E(2) related breast cancer; and (3) binding specificity of these methoxyflavonoids is based on the interactions between the methoxy groups and specific CYP1s residues.

• Authors: Hitomi Takemura, Toshimasa Itoh, Keiko Yamamoto, Hiroyuki Sakakibara, Kayoko Shimoi
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 17 Pg. 6310-5 (Sep 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20696580 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 Enzyme Inhibitors
• Flavonoids
• Cytochrome P-450 Enzyme System
• Aryl Hydrocarbon Hydroxylases
• CYP1B1 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 CYP1B1

Topics

• Aryl Hydrocarbon Hydroxylases
• Cytochrome P-450 CYP1A1 (antagonists & inhibitors, chemistry, metabolism)
• Cytochrome P-450 CYP1A2 (chemistry, metabolism)
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1B1
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (chemistry, metabolism)
• Flavonoids (chemistry, metabolism, pharmacology)
• Humans
• Models, Molecular
• Structure-Activity Relationship