title: The metabolism of the piperazine-type phenothiazine neuroleptic perazine by the human cytochrome P-450 isoenzymes.
abstract: Identification of cytochrome P-450 isoenzymes (CYPs) involved in perazine 5-sulphoxidation and N-demethylation was carried out using human liver microsomes and cDNA-expressed human CYPs (Supersomes). In human liver microsomes, the formation of perazine metabolites correlated significantly with the level of CYP1A2 and ethoxyrezorufin O-deethylase activity, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylperazine also correlated well with S-mephenytoin 4'-hydroxylase activity (CYP2C19). alpha-Naphthoflavone (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of perazine 5-sulphoxidation, while ticlopidine (a CYP2C19 inhibitor) strongly reduced the rate of perazine N-demethylation in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of perazine metabolites, but the preference of CYP isoforms to catalyze perazine metabolism was as follows (pmol of product/pmol of CYP isoform/min): 1A1>2D6>2C19>1A2>2B6>2E1>2A6 approximately 3A4>2C9 for 5-sulphoxidation and 2C19>2D6>1A1>1A2>2B6>3A4>2C9>2A6 for N-demethylation. In the light of the obtained results and regarding the contribution of each isoform to the total amount of CYP in human liver, it is concluded that CYP1A2 and CYP3A4 are the main isoenzymes catalyzing 5-sulphoxidation (32% and 30%, respectively), while CYP2C19 is the main isoform catalyzing perazine N-demethylation (68%). CYP2C9, CYP2E1 CYP2C19 and CYP2D6 are engaged to a lesser degree in 5-sulphoxidation, while CYP1A2, CYP3A4 and CYP2D6 in perazine N-demethylation (6-10%, depending on the isoform).
authors.affiliation: Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343, Cracow, Poland. wojcikow@if-pan.krakow.pl
authors.forename: Jacek
authors.initials: J
authors.lastname: Wójcikowski
authors.forename: Lydiane
authors.initials: L
authors.lastname: Pichard-Garcia
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Władysława A
authors.initials: WA
authors.lastname: Daniel
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism*; D001571:Benzoflavones / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000502:physiology*; D018076:DNA, Complementary; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010464:Perazine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010640:Phenothiazines / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001571:Benzoflavones; D018076:DNA, Complementary; D007527:Isoenzymes; D010640:Phenothiazines; D011994:Recombinant Proteins; C017636:10-piperazinylpropylphenothiazine; C011512:alpha-naphthoflavone; D010464:Perazine; D003577:Cytochrome P-450 Enzyme System; D010089:Oxidoreductases, N-Demethylating