title: Characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine.
abstract: The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.
authors.affiliation: Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343 Kraków, Poland. wojcikow@if-pan.krakow.pl
authors.forename: Jacek
authors.initials: J
authors.lastname: Wójcikowski
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Władysława A
authors.initials: WA
authors.lastname: Daniel
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002384:Catalysis; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007313:Insecta; D008862:Microsomes, Liver / Q000201:enzymology*; D010880:Piperidines / Q000378:metabolism / Q000493:pharmacokinetics*; D013881:Thioridazine / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D014150:Antipsychotic Agents; D010880:Piperidines; D003577:Cytochrome P-450 Enzyme System; D013881:Thioridazine