Oxidation of 3’-methoxyflavone, 4’-methoxyflavone, and 3’,4’-dimethoxyflavone and their derivatives having 5,7-dihydroxyl moieties by human cytochromes P450 1B1 and 2A13

Abstract

1. Oxidation of 3’-methoxyflavone, 4’-methoxyflavone, and 3’,4’-dimethoxyflavone and their derivatives containing 5,7-dihydroxyl groups by human cytochrome P450 (P450 or CYP) 1B1 and 2A13 was determined using LC-MS/MS systems.

2. 3’-Methoxyflavone and 4’-methoxyflavone were mainly O-demethylated to form 3’-hydroxyflavone and 4’-hydroxyflavone, respectively, and then 3’,4’-dihydroxyflavone at higher rates with CYP1B1 than with CYP2A13. 4’-Methoxy-5,7-dihydroxyflavone (acacetin) was found to be demethylated by CYP1B1 and 2A13 to form 4’,5,7-trihydroxyflavone (apigenin) at rates of 0.098⁻¹ and 0.42 min⁻¹, respectively. 3’-Methoxy-5,7-dihydroxyflavone was also demethylated by both P450s, with CYP2A13 being more active.

3. 3’,4’-Dimethoxyflavone was a good substrate for CYP1B1 but not for CYP2A13 and was found to be mainly O-demethylated to form 3’,4’-dihydroxyflavone (at a rate of 4.2 min⁻¹) and also several ring-oxygenated products having m/z 299 fragments. Molecular docking analysis supported the proper orientation for formation of these products by CYP1B1.

4. Our present results showed that 3’- and 4’-methoxyflavone can be oxidised to their O-demethylated products and, to a lesser extent, to ring oxidation products by both P450s 1B1 and 2A13 and that 3’,4’-dimethoxyflavone is a good substrate for CYP1B1 in forming both O-demethylated and ring-oxidation products. Introduction of a 57diOHF moiety into these methoxylated flavonoids caused decreased in oxidation by CYP1B1 and 2A13.

Keywords:

• LC-MS/MS
• 3’,4’-dimethoxyflavone
• methoxylated flavones
• oxidation
• CYP1B1
• CYP2A13

Acknowledgements

The authors thank Dr. Maryam Foroozesh for her supply of flavonoid derivatives used in this study.

Disclosure statement

The authors report no declarations of interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was supported in part by JSPS KAKENHI [16K21710] (to H. N), [17K08426] (to N. M.), [17K08425] (to H. Y.), and [15K07770] (to S. T.), National Research Foundation of Korea [NRF-2016R1D1A1B03932002] (to D. K.), and United States Public Health Service grant [R01 GM118122] (to F. P. G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.