RT Journal Article
SR Electronic
T1 Identification of 19-(S/R)Hydroxyeicosatetraenoic Acid as the First Endogenous Non-Competitive Inhibitor of Cytochrome P450 CYP1B1 with Enantioselective Activity
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.084657
DO 10.1124/dmd.118.084657
A1 Sherif M. Shoieb
A1 Ahmed A. El-Sherbeni
A1 Ayman O.S. El-Kadi
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/11/12/dmd.118.084657.abstract
AB The overexpression of cytochrome P450 1B1 (CYP1B1) is a common characteristic of several diseases and conditions, such as inflammation, cancer and cardiac hypertrophy. CYP1B1 is believed to contribute to pathogenesis of these diseases by mediating the formation of toxic compounds, either from exogenous or endogenous origin. We recently reported that an arachidonic acid metabolite, 19(S/R-)hydroxyeicosatetraenoic (HETE) acid, protects from cardiac hypertrophy by inhibiting the formation of toxic compounds, midchain HETEs, known to be formed by CYP1B1. This raised the question whether 19(S/R)-HETE can directly inhibit CYP1B1. In the current study, we are reporting that 19(S/R)-HETE enantioselectively inhibits human recombinant CYP1B1 activity measured by 7-ethoxyresorufin O deethylation assay. 19(S)-HETE is more potent than the R enantiomer (Ki = 37.3 and 89.1 nM, respectively). Non-competitive inhibition was identified as the mechanism of CYP1B1 inhibition, which underlines the potentially important physiological role of 19(S/R)-HETE as an endogenous CYP1B1 inhibitor; to our knowledge, 19(S/R)-HETE is the first inhibitor of its kind to be reported.