HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme

Br J Pharmacol. 2001 Jun;133(3):325-9. doi: 10.1038/sj.bjp.0704101.

Abstract

The present study examined the inhibitory effects of N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in rat renal microsomes. The IC(50) value averaged 35+/-4 nM, whereas the IC(50) value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800+/-300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20-HETE with an IC(50) value of 8.9+/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC(50) values of 3300, 83,900 and 71,000 nM. The IC(50) value for HET0016 on cyclo-oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20-HETE in man and rat.

MeSH terms

  • Amidines / chemistry
  • Amidines / pharmacology*
  • Animals
  • Arachidonic Acid / metabolism*
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Kidney / drug effects
  • Kidney / enzymology
  • Kidney / metabolism
  • Male
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Microsomes / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / metabolism
  • Rats
  • Rats, Inbred SHR
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / antagonists & inhibitors
  • Steroid Hydroxylases / metabolism

Substances

  • Amidines
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • HET0016
  • Hydroxyeicosatetraenoic Acids
  • Arachidonic Acid
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • Steroid 16-alpha-Hydroxylase
  • CYP3A4 protein, human