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Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites.
Chem Res Toxicol. 2006 Jul; 19(7):914-20.CR

Abstract

Haloperidol (HP) has been reported to undergo cytochrome P450 (P450)-mediated metabolism to potentially neurotoxic pyridinium metabolites; however, the chemical pathways and specific enzymes involved in these reactions remain to be identified. The aims of the current study were to (i) fully identify the cytochrome P450 enzymes capable of metabolizing HP to the pyridinium metabolite, 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutylpyridinium (HPP(+)), and reduced HP (RHP) to 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP(+)); and (ii) determine whether 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutyl-1,2,3,6-tetrahydropyridine (HPTP) and 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutyl-1,2,3,6-tetrahydropyridine (RHPTP) were metabolic intermediates in these pathways. In vitro studies were conducted using human liver microsomal preparations and recombinant human cytochrome P450 enzymes (P450s 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19 2D6, 2E1, 3A4, 3A5, and 3A7) expressed in bicistronic format with human NADPH cytochrome P450 reductase in Escherichia coli membranes. Pyridinium formation from HP and RHP was highly correlated across liver preparations, suggesting the same enzyme or enzymes were responsible for both reactions. Cytochrome P450s 3A4, 3A5, and 3A7 were the only recombinant enzymes which demonstrated significant catalytic activity under optimized conditions, although trace levels of activity could be catalyzed by NADPH-P450 reductase alone. NADPH-P450 reductase-mediated activity was inhibited by reduced glutathione but not catalase or superoxide dismutase, suggesting O(2)-dependent oxidation. No evidence was obtained to support the contention that HPTP and RHPTP are intermediates in these pathways. K(m) values for HPP(+) (34 +/- 5 microM) and RHPP(+) (64 +/- 4 microM) formation by recombinant P450 3A4 agreed well with those obtained with human liver microsomes, consistent with P450 3A4 being the major catalyst of pyridinium metabolite formation in human liver.

Authors+Show Affiliations

Avent KM
School of Biomedical Sciences, and School of Molecular and Microbial Sciences, The University of Queensland, Brisbane, Australia.
DeVoss JJ
No affiliation info available
Gillam EM
No affiliation info available

MeSH

BiotransformationCatalysisCytochrome P-450 Enzyme SystemHaloperidolHumansMicrosomes, LiverModels, BiologicalMutationOxidation-ReductionPyridinium CompoundsRecombinant Proteins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16841959

Citation

Avent, Kathryn M., et al. "Cytochrome P450-mediated Metabolism of Haloperidol and Reduced Haloperidol to Pyridinium Metabolites." Chemical Research in Toxicology, vol. 19, no. 7, 2006, pp. 914-20.
Avent KM, DeVoss JJ, Gillam EM. Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites. Chem Res Toxicol. 2006;19(7):914-20.
Avent, K. M., DeVoss, J. J., & Gillam, E. M. (2006). Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites. Chemical Research in Toxicology, 19(7), 914-20.
Avent KM, DeVoss JJ, Gillam EM. Cytochrome P450-mediated Metabolism of Haloperidol and Reduced Haloperidol to Pyridinium Metabolites. Chem Res Toxicol. 2006;19(7):914-20. PubMed PMID: 16841959.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites. AU - Avent,Kathryn M, AU - DeVoss,J J, AU - Gillam,Elizabeth M J, PY - 2006/7/18/pubmed PY - 2006/10/17/medline PY - 2006/7/18/entrez SP - 914 EP - 20 JF - Chemical research in toxicology JO - Chem Res Toxicol VL - 19 IS - 7 N2 - Haloperidol (HP) has been reported to undergo cytochrome P450 (P450)-mediated metabolism to potentially neurotoxic pyridinium metabolites; however, the chemical pathways and specific enzymes involved in these reactions remain to be identified. The aims of the current study were to (i) fully identify the cytochrome P450 enzymes capable of metabolizing HP to the pyridinium metabolite, 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutylpyridinium (HPP(+)), and reduced HP (RHP) to 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP(+)); and (ii) determine whether 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutyl-1,2,3,6-tetrahydropyridine (HPTP) and 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutyl-1,2,3,6-tetrahydropyridine (RHPTP) were metabolic intermediates in these pathways. In vitro studies were conducted using human liver microsomal preparations and recombinant human cytochrome P450 enzymes (P450s 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19 2D6, 2E1, 3A4, 3A5, and 3A7) expressed in bicistronic format with human NADPH cytochrome P450 reductase in Escherichia coli membranes. Pyridinium formation from HP and RHP was highly correlated across liver preparations, suggesting the same enzyme or enzymes were responsible for both reactions. Cytochrome P450s 3A4, 3A5, and 3A7 were the only recombinant enzymes which demonstrated significant catalytic activity under optimized conditions, although trace levels of activity could be catalyzed by NADPH-P450 reductase alone. NADPH-P450 reductase-mediated activity was inhibited by reduced glutathione but not catalase or superoxide dismutase, suggesting O(2)-dependent oxidation. No evidence was obtained to support the contention that HPTP and RHPTP are intermediates in these pathways. K(m) values for HPP(+) (34 +/- 5 microM) and RHPP(+) (64 +/- 4 microM) formation by recombinant P450 3A4 agreed well with those obtained with human liver microsomes, consistent with P450 3A4 being the major catalyst of pyridinium metabolite formation in human liver. SN - 0893-228X UR - https://www.unboundmedicine.com/medline/citation/16841959/Cytochrome_P450_mediated_metabolism_of_haloperidol_and_reduced_haloperidol_to_pyridinium_metabolites_ DB - PRIME DP - Unbound Medicine ER -