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Contribution of human cytochrome p-450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine.
Br J Pharmacol. 2003 Apr; 138(8):1465-74.BJ

Abstract

1. The aim of the present study was to identify human cytochrome p-450 isoforms (CYPs) involved in 5-sulphoxidation and N-demethylation of the simplest phenothiazine neuroleptic promazine in human liver. 2. The experiments were performed in the following in vitro models: (A). a study of promazine metabolism in liver microsomes-(a). correlations between the rate of promazine metabolism and the level and activity of CYPs; (b). the effect of specific inhibitors on the rate of promazine metabolism (inhibitors: CYP1A2-furafylline, CYP2D6-quinidine, CYP2A6+CYP2E1-diethyldithiocarbamic acid, CYP2C9-sulfaphenazole, CYP2C19-ticlopidine, CYP3A4-ketoconazole); (B). promazine biotransformation by cDNA-expressed human CYPs (Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4); (C). promazine metabolism in a primary culture of human hepatocytes treated with specific inducers (rifampicin-CYP3A4, CYP2B6 and CYP2C inducer, 2,3,7,8-tetrachlordibenzeno-p-dioxin (TCDD)-CYP1A1/1A2 inducer). 3. In human liver microsomes, the formation of promazine 5-sulphoxide and N-desmethylpromazine was significantly correlated with the level of CYP1A2 and ethoxyresorufin O-deethylase and acetanilide 4-hydroxylase activities, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylpromazine was correlated well with S-mephenytoin 4'-hydroxylation. 4. Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5-sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine N-demethylation in human liver microsomes. 5. The cDNA-expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 microM) was as follows: 1A1>2B6>1A2>2C9>3A4>2E1>2A6>2D6>2C19 for 5-sulphoxidation and 2C19>2B6>1A1>1A2>2D6>3A4>2C9>2E1>2A6 for N-demethylation. The highest intrinsic clearance (V(max)/K(m)) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5- sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of N-demethylation. 6. In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5-sulphoxide and N-desmethylpromazine. 7. Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5-sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse N-demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5-sulphoxidation and N-demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible.

Authors+Show Affiliations

Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland. wojcikow@if-pan.krakow.plNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12721102

Citation

Wójcikowski, Jacek, et al. "Contribution of Human Cytochrome P-450 Isoforms to the Metabolism of the Simplest Phenothiazine Neuroleptic Promazine." British Journal of Pharmacology, vol. 138, no. 8, 2003, pp. 1465-74.
Wójcikowski J, Pichard-Garcia L, Maurel P, et al. Contribution of human cytochrome p-450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine. Br J Pharmacol. 2003;138(8):1465-74.
Wójcikowski, J., Pichard-Garcia, L., Maurel, P., & Daniel, W. A. (2003). Contribution of human cytochrome p-450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine. British Journal of Pharmacology, 138(8), 1465-74.
Wójcikowski J, et al. Contribution of Human Cytochrome P-450 Isoforms to the Metabolism of the Simplest Phenothiazine Neuroleptic Promazine. Br J Pharmacol. 2003;138(8):1465-74. PubMed PMID: 12721102.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contribution of human cytochrome p-450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine. AU - Wójcikowski,Jacek, AU - Pichard-Garcia,Lydiane, AU - Maurel,Patrick, AU - Daniel,Władysława A, PY - 2003/5/2/pubmed PY - 2004/1/6/medline PY - 2003/5/2/entrez SP - 1465 EP - 74 JF - British journal of pharmacology JO - Br J Pharmacol VL - 138 IS - 8 N2 - 1. The aim of the present study was to identify human cytochrome p-450 isoforms (CYPs) involved in 5-sulphoxidation and N-demethylation of the simplest phenothiazine neuroleptic promazine in human liver. 2. The experiments were performed in the following in vitro models: (A). a study of promazine metabolism in liver microsomes-(a). correlations between the rate of promazine metabolism and the level and activity of CYPs; (b). the effect of specific inhibitors on the rate of promazine metabolism (inhibitors: CYP1A2-furafylline, CYP2D6-quinidine, CYP2A6+CYP2E1-diethyldithiocarbamic acid, CYP2C9-sulfaphenazole, CYP2C19-ticlopidine, CYP3A4-ketoconazole); (B). promazine biotransformation by cDNA-expressed human CYPs (Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4); (C). promazine metabolism in a primary culture of human hepatocytes treated with specific inducers (rifampicin-CYP3A4, CYP2B6 and CYP2C inducer, 2,3,7,8-tetrachlordibenzeno-p-dioxin (TCDD)-CYP1A1/1A2 inducer). 3. In human liver microsomes, the formation of promazine 5-sulphoxide and N-desmethylpromazine was significantly correlated with the level of CYP1A2 and ethoxyresorufin O-deethylase and acetanilide 4-hydroxylase activities, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylpromazine was correlated well with S-mephenytoin 4'-hydroxylation. 4. Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5-sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine N-demethylation in human liver microsomes. 5. The cDNA-expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 microM) was as follows: 1A1>2B6>1A2>2C9>3A4>2E1>2A6>2D6>2C19 for 5-sulphoxidation and 2C19>2B6>1A1>1A2>2D6>3A4>2C9>2E1>2A6 for N-demethylation. The highest intrinsic clearance (V(max)/K(m)) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5- sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of N-demethylation. 6. In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5-sulphoxide and N-desmethylpromazine. 7. Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5-sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse N-demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5-sulphoxidation and N-demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/12721102/Contribution_of_human_cytochrome_p_450_isoforms_to_the_metabolism_of_the_simplest_phenothiazine_neuroleptic_promazine_ L2 - https://doi.org/10.1038/sj.bjp.0705195 DB - PRIME DP - Unbound Medicine ER -