Inhibitory effects of dietary flavonoids on purified hepatic NADH-cytochrome b5 reductase: structure-activity relationships

Chem Biol Interact. 2012 May 30;197(2-3):103-9. doi: 10.1016/j.cbi.2012.04.003. Epub 2012 Apr 19.

Abstract

The structure-activity relationships of flavonoids with regard to their inhibitory effects on NADH-cytochrome b5 reductase (E.C. 1.6.2.2), a clinically and toxicologically important enzyme, are not known. In the present study, the inhibitory effects of fourteen selected flavonoids of variable structure on the activity of purified bovine liver cytochrome b5 reductase, which shares a high degree of homology with the human counterpart, were investigated and the relationship between structure and inhibition was examined. Of all the compounds tested, the flavone luteolin was the most potent in inhibiting b5 reductase with an IC50 value of 0.11 μM, whereas naringenin, naringin and chrysin were inactive within the concentration range tested. Most of the remaining flavonoids (morin, quercetin, quercitrin, myricetin, luteolin-7-O-glucoside, (-)-epicatechin, and (+)-catechin) produced a considerable inhibition of enzyme activity with IC50 values ranging from 0.81 to 4.5 μM except apigenin (36 μM), rutin (57 μM) and (+)-taxifolin (IC50 not determined). The magnitude of inhibition was found to be closely related to the chemical structures of flavonoids. Analysis of structure-activity data revealed that flavonoids containing two hydroxyl groups in ring B and a carbonyl group at C-4 in combination with a double bond between C-2 and C-3 produced a much stronger inhibition, whereas substitution of a hydroxyl group at C-3 was associated with a less inhibitory effect. The physiologically relevant IC50 values for most of the flavonoids tested regarding b5 reductase inhibition indicate a potential for significant flavonoid-drug and/or flavonoid-xenobiotic interactions which may have important therapeutic and toxicological outcomes for certain drugs and/or xenobiotics.

MeSH terms

  • Animals
  • Catechin / chemistry
  • Catechin / pharmacology
  • Cattle
  • Cytochrome-B(5) Reductase / antagonists & inhibitors
  • Cytochrome-B(5) Reductase / metabolism*
  • Dietary Supplements
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Flavanones / chemistry
  • Flavanones / pharmacology
  • Flavones / chemistry
  • Flavones / pharmacology
  • Flavonoids / chemistry*
  • Flavonoids / pharmacology*
  • Glucosides / chemistry
  • Glucosides / pharmacology
  • Inhibitory Concentration 50
  • Microsomes, Liver / enzymology*
  • Quercetin / chemistry
  • Quercetin / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Flavanones
  • Flavones
  • Flavonoids
  • Glucosides
  • chrysin
  • morin
  • Catechin
  • luteolin-7-glucoside
  • Quercetin
  • Cytochrome-B(5) Reductase
  • naringin