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Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes.
Chem Res Toxicol. 1996 Jun; 9(4):800-6.CR

Abstract

The neuroleptic agent haloperidol (HP) and its tetrahydropyridine dehydration product HPTP are biotransformed to the potentially neurotoxic HP pyridinium species HPP+ and the reduced HP pyridinium species RHPP+ in humans and rodents. The studies reported here were designed to identify the specific form(s) of human cytochrome P450 that catalyze(s) these transformations. Fifteen human liver microsomal preparations all catalyzed the oxidation of HP and HPTP to HPP+ and HPTP to RHPP+. Values for kcat/KM averaged 6.71 and 1.24 min-1 mM-1 for HPP+ and RHPP+ formation, respectively. The rates of conversion of HP and HPTP to HPP+ correlated well with testosterone 6 beta-hydroxylase activity, a marker of P450 3A activity. Microsomes prepared from a human lymphoblastoid cell line co-expressing human P450 3A4 and cytochrome P450 reductase also catalyzed the formation of HPP+ from HP and HPTP. Troleandomycin and ketoconazole, potent P450 3A inhibitors, and antibodies against P450 3A were effective inhibitors of HPP+ formation. We conclude that the conversions of HP and HPTP to potentially neurotoxic pyridinium metabolite HPP+ are catalyzed selectively by P450 3A4 in human liver microsomes.

Authors+Show Affiliations

Usuki E
Department of Chemistry, Virginia Tech, Blacksburg 24061, USA.
Pearce R
No affiliation info available
Parkinson A
No affiliation info available
Castagnol N
No affiliation info available

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAnimalsAntibodiesAntipsychotic AgentsCalibrationChromatography, High Pressure LiquidCytochrome P-450 Enzyme SystemDose-Response Relationship, DrugEnzyme InhibitorsHaloperidolHumansKineticsMicrosomes, LiverOxidation-ReductionPyridinium CompoundsRatsSpectrometry, FluorescenceSteroid Hydroxylases

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8831826

Citation

Usuki, E, et al. "Studies On the Conversion of Haloperidol and Its Tetrahydropyridine Dehydration Product to Potentially Neurotoxic Pyridinium Metabolites By Human Liver Microsomes." Chemical Research in Toxicology, vol. 9, no. 4, 1996, pp. 800-6.
Usuki E, Pearce R, Parkinson A, et al. Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes. Chem Res Toxicol. 1996;9(4):800-6.
Usuki, E., Pearce, R., Parkinson, A., & Castagnol, N. (1996). Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes. Chemical Research in Toxicology, 9(4), 800-6.
Usuki E, et al. Studies On the Conversion of Haloperidol and Its Tetrahydropyridine Dehydration Product to Potentially Neurotoxic Pyridinium Metabolites By Human Liver Microsomes. Chem Res Toxicol. 1996;9(4):800-6. PubMed PMID: 8831826.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes. AU - Usuki,E, AU - Pearce,R, AU - Parkinson,A, AU - Castagnol,N,Jr PY - 1996/6/1/pubmed PY - 2001/3/28/medline PY - 1996/6/1/entrez SP - 800 EP - 6 JF - Chemical research in toxicology JO - Chem Res Toxicol VL - 9 IS - 4 N2 - The neuroleptic agent haloperidol (HP) and its tetrahydropyridine dehydration product HPTP are biotransformed to the potentially neurotoxic HP pyridinium species HPP+ and the reduced HP pyridinium species RHPP+ in humans and rodents. The studies reported here were designed to identify the specific form(s) of human cytochrome P450 that catalyze(s) these transformations. Fifteen human liver microsomal preparations all catalyzed the oxidation of HP and HPTP to HPP+ and HPTP to RHPP+. Values for kcat/KM averaged 6.71 and 1.24 min-1 mM-1 for HPP+ and RHPP+ formation, respectively. The rates of conversion of HP and HPTP to HPP+ correlated well with testosterone 6 beta-hydroxylase activity, a marker of P450 3A activity. Microsomes prepared from a human lymphoblastoid cell line co-expressing human P450 3A4 and cytochrome P450 reductase also catalyzed the formation of HPP+ from HP and HPTP. Troleandomycin and ketoconazole, potent P450 3A inhibitors, and antibodies against P450 3A were effective inhibitors of HPP+ formation. We conclude that the conversions of HP and HPTP to potentially neurotoxic pyridinium metabolite HPP+ are catalyzed selectively by P450 3A4 in human liver microsomes. SN - 0893-228X UR - https://www.unboundmedicine.com/medline/citation/8831826/Studies_on_the_conversion_of_haloperidol_and_its_tetrahydropyridine_dehydration_product_to_potentially_neurotoxic_pyridinium_metabolites_by_human_liver_microsomes_ L2 - https://doi.org/10.1021/tx960001y DB - PRIME DP - Unbound Medicine ER -