doi: 10.1038/sj.bjp.0704101.
HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme
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- PMID:11375247
- PMCID: PMC1572803
- DOI: 10.1038/sj.bjp.0704101
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HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme
N Miyata et al. Br J Pharmacol.2001 Jun.
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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.
Figures
Chemical structure of HET0016 (N-Hydroxy-N′-(4-butyl-2-methylphenyl)formamidine).
Effects of HET0016 (A), 17-ODYA (B) and 1-ABT (C) on the formation of 20-HETE and EETs by microsomes prepared from the kidneys of SHR. Results are expressed as per cent of control and are the mean±s.e.mean, respectivelyn=10–11.
Comparison of the effects of HET0016, 17-ODYA and 1-ABT on the production of 20-HETE in microsomes prepared from human kidneys. Results are expressed as per cent of control and are the mean±s.e.mean, respectivelyn=5–6.
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References
- ALONSO-GALICIA M., HUDETZ A.G., SHEN H., HARDER D.R., ROMAN R.J. Contribution of 20-HETE to vasodilator actions of nitric oxide in the cerebral microcirculation. Stroke. 1999;30:2727–2734. - PubMed
- CARROLL M.A., PILAR GRACIA M., FALCK J.R., MCGIFF J.C. Cycloxygenase dependency of the renovascular actions of cytochrome P450-derived arachidonic metabolites. J. Pharmacol. Exp. Ther. 1992;260:104–109. - PubMed
- CRESPI C.L., MILLER V.P., PENMAN B.W. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem. 1997;248:188–190. - PubMed
- GEBREMEDHIN D., LANGE A.R., LOWRY T.F., TAHERI M.R., BIRKS E.K., HUDERTZ A.G., NARAYANAN J., FALCK J.R., OKAMOTO H., ROMAN R.J., NITHIPATIKOM K., CAMPBELL W.B., HARDER D.R. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ. Res. 2000;87:60–65. - PubMed
- HARRIS R.C., HOMMA T., JACOBSEN H.R., CAPDEVILA J. Epoxyeicosatrienoic acids activate Na+/H+ exchange and are mitogenic in cultured rat glomerular mesangial cells. J. Cell. Physiol. 1990;144:429–437. - PubMed
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