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20-HETE is a major biologically active cytochrome P450 (CYP450) metabolite of arachidonic acid in the kidney and liver. It regulates renal vascular and tubular functions as well as vascular tone in the cerebral circulation.1,2,3,4,5 HET0016 is an inhibitor of 20-HETE formation in human renal microsomes with an IC50 of 8.9 nM, selectively inhibiting CYP4A and 4F isoforms.6,7 HET0016 inhibits CYP2C9, CYP2D6, and CYP3A4, enzymes important in drug metabolism, significantly less effectively with IC50s in the µM range. The IC50 values for inhibition of cyclooxygenase and epoxyeicosatrienoic acids (EETs) formation are 2.3 and 2.8 µM, respectively.6
1
Omata, K., Abraham, N.G., and Schwartzman, M.L. Renal cytochrome P-450-arachidonic acid metabolism: Localization and hormonal regulation in SHR. Am J Physiol Renal Fluid Electrolyte Physiol262F591-F599(1992).
2
Zou, A., Imig, J.D., Kaldunski, M., et al. Inhibition of renal vascular 20-HETE production impairs autoregulation of renal blood flow. Am J Physiol Renal Fluid Electrolyte Physiol35F275-F282(1994).
3
Lin, F., Rios, A., Falck, J.R., et al. 20-Hydroxyeicosatetraenoic acid is formed in response to EGF and is a mitogen in rat proximal tubule. Am J Physiol Renal Fluid Electrolyte Physiol38F806-F816(1995).
4
Imig, J.D., Zou, A., de Montellano, P.R.O., et al. Cytochrome P-450 inhibitors alter afferent arteriolar responses to elevations in pressure. Am J Physiol Heart Circ Physiol35H1879-H1885(1994).
5
Gebremedhin, D., Lange, A.R., Lowry, T.F., et al. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ Res8760-65(2000).
6
Miyata, N., Taniguchi, K., Seki, T., et al. HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme. Br J Pharmacol133325-329(2001).
7
Kehl, F., Cambj-Sapunar, L., Maier, K., et al. 20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat. Am J Physiol Heart Circ Physiol282H1556-H1565(2002).
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SMILES
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CCCCc1ccc(N\C=N\O)c(C)c1
Background Reading
Omata, K., Abraham, N.G., and Schwartzman, M.L. Renal cytochrome P-450-arachidonic acid metabolism: Localization and hormonal regulation in SHR. Am J Physiol Renal Fluid Electrolyte Physiol262F591-F599(1992).
Imig, J.D., Zou, A., de Montellano, P.R.O., et al. Cytochrome P-450 inhibitors alter afferent arteriolar responses to elevations in pressure. Am J Physiol Heart Circ Physiol35H1879-H1885(1994).
Miyata, N., Taniguchi, K., Seki, T., et al. HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme. Br J Pharmacol133325-329(2001).
Kehl, F., Cambj-Sapunar, L., Maier, K., et al. 20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat. Am J Physiol Heart Circ Physiol282H1556-H1565(2002).
Gebremedhin, D., Lange, A.R., Lowry, T.F., et al. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ Res8760-65(2000).
Lin, F., Rios, A., Falck, J.R., et al. 20-Hydroxyeicosatetraenoic acid is formed in response to EGF and is a mitogen in rat proximal tubule. Am J Physiol Renal Fluid Electrolyte Physiol38F806-F816(1995).
Zou, A., Imig, J.D., Kaldunski, M., et al. Inhibition of renal vascular 20-HETE production impairs autoregulation of renal blood flow. Am J Physiol Renal Fluid Electrolyte Physiol35F275-F282(1994).