The present study examined the inhibitory eects 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.
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