Microsomal cytochrome P450 as a target for drug discovery and repurposing.
Cytochrome P450 (P450) enzymes are ancient electron-transfer-chain system of remarkable biological importance. Microsomal P450 enzymes are the P450 attached to endoplasmic reticulum, which, in humans, are critical for body's defenses against xenobiotics by mediating their metabolism, and cell signaling by mediating arachidonic acid (AA) transformation to several potent bioactive molecules. Only recently, modulating P450-mediated AA metabolism has risen as a promising new drug target. This review presents the therapeutic potential of finding effective, selective and safe treatments targeting P450-mediated AA metabolism, and the several approaches that have been used to find these treatments; among which, our focus was on modulators of P450 activities. We detailed the efforts done to develop new molecular entities designed to modulate P450, and the more recent efforts tried to employ our previous knowledge on drug metabolism to repurpose old drugs with the capacity to alter P450-mediated drug metabolism to target AA metabolism. Because of the long recognition of P450 role in xenobiotic metabolism, several clinically approved agents were identified to alter P450 activity. Repurposing old drugs as P450 modulators can facilitate bringing treatments targeting P450-mediated AA metabolism to clinical trials. However, the capacity of the modulation of P450-derived AA metabolites of clinically approved drugs has to be systematically investigated and validated for their new use in humans.
a Faculty of Pharmacy and Pharmaceutical Sciences , 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta , Edmonton , Alberta , Canada.
Ahmed A
AA
El-Sherbeni
a Faculty of Pharmacy and Pharmaceutical Sciences , 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta , Edmonton , Alberta , Canada.
Ayman O S
AO
El-Kadi
D016718:Arachidonic Acid / Q000378:metabolism / Q000502:physiology; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D055808:Drug Discovery; D004347:Drug Interactions; D058492:Drug Repositioning; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006801:Humans; D008861:Microsomes / Q000201:enzymology*
D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases
Cytochrome P450; arachidonic acid; drug discovery; drug repurposing; polyunsaturated fatty acids