Isozyme- and species-specific susceptibility of cDNA-expressed CYP1A P-450s to different flavonoids

Ilya B. Tsyrlov, Victor M. Mikhailenko, Harry V. Gelboin

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

The inhibitory and stimulatory effects of six flavonoids with distinct hydroxylation patterns on the recombinant and hepatic mouse and human CYP1A P-450s were studied cDNA-expressed mouse CYP1A1 and CYP1A2 differed in their sensitivity to both hydroxylated and nonhydroxylated flavonoids, respectively. A comparison between the mouse and human CYP1A2 revealed that α-naphthoflavone and flavone did not change the benzo[α]pyrene 3-hydroxylation activity of human CYP1A2 but inhibited its 7-ethoxyresorufin and 7-methoxyresorufin O-dealkylation activities. In contrast, hydroxylated flavonoids increased the 7-methoxyresorufin O-demethylation and acetanilide 4-hydroxylation activities of cDNA-expressed human CYPIA2 and in human liver microsomes. These compounds inhibited the benzo[α]pyrene 3-hydroxylase activity of cDNA-expressed CYP1A1 and CYP1A2s as well as in mouse and human liver microsomes. Hydroxylated flavonoids did not inhibit NADPH-cytochrome P-450 oxidoreductase activity but inhibited NADPH-2,6-dichlorophenolindophenol oxidoreductase activity in liver microsomes and in microsomes from recombinant Hep G2 cells. Structure-activity relationships indicated the importance of hydroxyl groups in the 5- and 7-positions on the A ring of the flavane nucleus. These hydroxyl groups accounted for the inhibitory potency of chrysin on each of the activities of the expressed P-450(rms, while presence of a hydroxyl group at the 4'-position on the B ring decreased the inhibitory potency of naringenin compared to that of chrysin. The ortho-orientation of a hydroxyl group on the B ring was of importance, inasmuch as quercetin was more potent than morin as an inhibitor of cDNA-expressed and hepatic microsomal monooxygenases.

Original languageEnglish
Pages (from-to)325-335
Number of pages11
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1205
Issue number2
DOIs
StatePublished - 13 Apr 1994
Externally publishedYes

Keywords

  • (Human)
  • Activation (Mouse)
  • Flavonoid
  • Hepatic cytochrome
  • Inhibition
  • cDNA-expressed cytochrome

Fingerprint

Dive into the research topics of 'Isozyme- and species-specific susceptibility of cDNA-expressed CYP1A P-450s to different flavonoids'. Together they form a unique fingerprint.

Cite this