title: Cytochrome P450 isoforms responsible for the N-deethylation and cyclohexane-hydroxylation of NS-21.
abstract: 1. Cytochrome P450 (P450) isoforms responsible for the N-deethylation and cyclohexane-hydroxylation of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21) have been identified in rat and man. 2. Anti-CYP2C11 antibody inhibited the N-deethylation of S- and R-NS-21 in rat hepatic microsomes by 84 and 66% respectively, indicating that CYP2C11 is mainly responsible for these activities in male rats. 3. Of several human recombinant P450 isoforms, CYP3A4 had the activities for the N-deethylation of S- and R-NS-21. In addition, triacetyloleandomycin (TAO), an inhibitor of the CYP3A subfamily, significantly inhibited the N-deethylation of S- and R-NS-21 in human hepatic microsomes by 67 and 69%, respectively. CYP3A4 therefore contributes to it in man. 4. Quinine, an inhibitor of the rat CYP2D subfamily, significantly inhibited the cyclohexane-4-cis-hydroxylation of S-NS-21 by 48% in rat hepatic microsomes. In contrast, this inhibitor had little effect on the cyclohexane-4-trans-hydroxylation of S-NS-21, and the cyclohexane-4-cis- and trans-hydroxylation of R-NS-21. 5. Human recombinant CYP3A4 catalysed the cyclohexane-4-trans-hydroxylation of S-NS-21, and CYP2D6 supported the cyclohexane-4-cis- and trans-hydroxylation of S-NS-21. Quinidine, an inhibitor of human CYP2D6, had little effect on these latter activities in human hepatic microsomes. TAO significantly inhibited the cyclohexane-4-trans-hydroxylation of S-NS-21 by 75%, indicating that CYP3A4 catalyses this reaction.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Hirota
authors.forename: A
authors.initials: A
authors.lastname: Morino
authors.forename: S
authors.initials: S
authors.lastname: Imaoka
authors.forename: Y
authors.initials: Y
authors.lastname: Funae
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Tasaki
authors.forename: M
authors.initials: M
authors.lastname: Masuda
authors.forename: A
authors.initials: A
authors.lastname: Kazusaka
authors.forename: S
authors.initials: S
authors.lastname: Fujita
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000378:metabolism*; D003510:Cyclohexanes / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000276:immunology / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D000906:Antibodies; D002121:Calcium Channel Blockers; D018680:Cholinergic Antagonists; D003510:Cyclohexanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010648:Phenylacetates; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C105354:temiverine; D011803:Quinine; D014217:Troleandomycin; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D011802:Quinidine