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HET0016, a potent and selective inhibitor of 20‐HETE synthesizing enzyme
Author(s) -
Miyata Noriyuki,
Taniguchi Kazuo,
Seki Takayuki,
Ishimoto Tsuyoshi,
SatoWatanabe Mariko,
Yasuda Yoshiko,
Doi Mariko,
Kametani Shunichi,
Tomishima Yasumitsu,
Ueki Tomokazu,
Sato Masakazu,
Kameo Kazuya
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704101
Subject(s) - microsome , enzyme , arachidonic acid , cytochrome p450 , chemistry , metabolism , cyp3a4 , biochemistry , enzyme kinetics , active site
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 n M , whereas the IC 50 value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800±300 n M . In human renal microsomes, HET0016 potently inhibited the formation of 20‐HETE with an IC 50 value of 8.9±2.7 n M . 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 n M . The IC 50 value for HET0016 on cyclo‐oxygenase activity was 2300 n M . 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. British Journal of Pharmacology (2001) 133 , 325–329; doi: 10.1038/sj.bjp.0704101