title: Role of CYP2E1 in deramciclane metabolism.
abstract: The aim of our study was to identify the form(s) of cytochrome P450 responsible for the metabolism of deramciclane, a new anxiolytic drug candidate. The main routes of biotransformation in hepatic microsomes were side chain modification (N-demethylation or total side chain cleavage) and hydroxylation at several points of the molecule. Although several cytochrome P450 forms were involved in the metabolism, the role of CYP2E1 should be emphasized, since it catalyzed almost all steps. Production of deramciclane metabolites was significantly inhibited by diethyl-dithiocarbamate and was elevated in liver microsomes of isoniazid-treated rats. Furthermore, cDNA-expressed rat CYP2E1 generated the metabolites formed by side chain modification and hydroxylation. Neither deramciclane nor its primary metabolite, N-desmethyl deramciclane were able to influence directly the activity of CYP2E1. However, during the biotransformation, one or more metabolites must have been formed which were potent inhibitors of CYP2E1.
authors.affiliation: Chemical Research Center, Hungarian Academy of Sciences, Hungary. monostor@chemres.hu
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
authors.forename: Krisztina
authors.initials: K
authors.lastname: Köhalmy
authors.forename: Eszter
authors.initials: E
authors.lastname: Hazai
authors.forename: László
authors.initials: L
authors.lastname: Vereczkey
authors.forename: László
authors.initials: L
authors.lastname: Kóbori
mesh_terms: D000818:Animals; D001892:Camphanes / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004050:Ditiocarb / Q000494:pharmacology; D004790:Enzyme Induction; D007538:Isoniazid / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001892:Camphanes; D065691:Cytochrome P-450 CYP2E1 Inhibitors; C406721:N-desmethylderamciclane; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; C060555:deramciclane; D007538:Isoniazid