Site-specific oxidation of flavanone and flavone by cytochrome P450 2A6 in human liver microsomes
Creators: name: Nagayoshi, Haruna
name: Murayama, Norie
name: Kakimoto, Kensaku
name: Takenaka, Shigeo
name: Katahira, Jun
name: Lim, Young-Ran
name: Vitchan Kim
name: Donghak Kim
name: Yamazaki, Hiroshi
name: Komori, Masayuki
name: F. Peter Guengerich
name: Shimada, Tsutomu
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biochemistry
subject: Space Science
subject: Molecular Biology
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Evolutionary Biology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Ecology
subject: Sociology
subject: FOS: Sociology
subject: FOS: Sociology
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: Science Policy
subject: Hematology
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences

description: The roles of human cytochrome P450 (P450 or CYP) 2A6 in the oxidation of flavanone [(<i>2R</i>)- and (<i>2S</i>)-enantiomers] and flavone were studied in human liver microsomes and recombinant human P450 enzymes.CYP2A6 was highly active in oxidizing flavanone to form flavone, 2′-hydroxy-, 4′-, and 6-hydroxyflavanones and in oxidizing flavone to form mono- and di-hydroxylated products, such as mono-hydroxy flavones M6, M7, and M11 and di-hydroxy flavones M3, M4, and M5.Liver microsomes prepared from human sample HH2, defective in coumarin 7-hydroxylation activity, were very inefficient in forming 2′-hydroxyflavanone from flavanone and a mono-hydroxylated product, M6, from flavone. Coumarin and anti-CYP2A6 antibodies strongly inhibited the formation of these metabolites in microsomes prepared from liver samples HH47 and 54, which were active in coumarin oxidation activities.Molecular docking analysis showed that the C2′-position of (<i>2R</i>)-flavanone (3.8 Å) was closer to the iron center of CYP2A6 than the C6-position (10 Å), while distances from C2′ and C6 of (<i>2S</i>)-flavanone to the CYP2A6 were 6.91 Å and 5.42 Å, respectively.These results suggest that CYP2A6 catalyzes site-specific oxidation of (racemic) flavanone and also flavone in human liver microsomes. CYP1A2 and CYP2B6 were also found to play significant roles in some of the oxidations of these flavonoids by human liver microsomes. The roles of human cytochrome P450 (P450 or CYP) 2A6 in the oxidation of flavanone [(<i>2R</i>)- and (<i>2S</i>)-enantiomers] and flavone were studied in human liver microsomes and recombinant human P450 enzymes. CYP2A6 was highly active in oxidizing flavanone to form flavone, 2′-hydroxy-, 4′-, and 6-hydroxyflavanones and in oxidizing flavone to form mono- and di-hydroxylated products, such as mono-hydroxy flavones M6, M7, and M11 and di-hydroxy flavones M3, M4, and M5. Liver microsomes prepared from human sample HH2, defective in coumarin 7-hydroxylation activity, were very inefficient in forming 2′-hydroxyflavanone from flavanone and a mono-hydroxylated product, M6, from flavone. Coumarin and anti-CYP2A6 antibodies strongly inhibited the formation of these metabolites in microsomes prepared from liver samples HH47 and 54, which were active in coumarin oxidation activities. Molecular docking analysis showed that the C2′-position of (<i>2R</i>)-flavanone (3.8 Å) was closer to the iron center of CYP2A6 than the C6-position (10 Å), while distances from C2′ and C6 of (<i>2S</i>)-flavanone to the CYP2A6 were 6.91 Å and 5.42 Å, respectively. These results suggest that CYP2A6 catalyzes site-specific oxidation of (racemic) flavanone and also flavone in human liver microsomes. CYP1A2 and CYP2B6 were also found to play significant roles in some of the oxidations of these flavonoids by human liver microsomes.