title: Inhibition of CYP2B4 by the mechanism-based inhibitor 2-ethynylnaphthalene: inhibitory potential of 2EN is dependent on the size of the substrate.
abstract: 2-Ethynylnaphthalene (2EN) is a mechanism-based inhibitor of CYP2B4 with two components to the inhibition, (1) enzyme inactivation, which requires covalent binding of the 2EN metabolite, and (2) reversible inhibition by 2EN itself. Both inhibitory components were examined using several different CYP2B4 substrates. Preincubation of CYP2B4 with 2EN led to a time-dependent inactivation of each of the CYP2B4-dependent activities examined; however, the ability of 2EN to reversibly inhibit CYP2B4 depended on the substrate employed, which is inconsistent with classical inhibition patterns. The degree 2EN's reversible inhibition was shown not to correlate with the substrate affinity for the active site, but with parameters related to the molecular size of the substrate. The results are consistent with 2EN and the smaller substrates simultaneously fitting in the CYP2B4 active site, leading to very little inhibition. Larger substrates exhibited greater degrees of inhibition because of their inability to co-bind with inhibitor in the active site.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, and The Stanley S Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: James R
authors.initials: JR
authors.lastname: Reed
authors.forename: Danni
authors.initials: D
authors.lastname: Harris
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Backes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008956:Models, Chemical; D009281:Naphthalenes / Q000494:pharmacology*; D011817:Rabbits; D012984:Software; D013050:Spectrometry, Fluorescence; D013379:Substrate Specificity; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; C065012:2-ethynylnaphthalene; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit)