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