Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation.
OBJECTIVE
The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/- cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated.


RESULTS
The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The kM value for the CYP3A4 expressed in the cells was 69.7 micromol x l(-1), and the Vmax was 4.87 pmol x min(-1) x pmol(-1) P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k(i) value of 24.9 and 1390 micromol x l(-1), respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k(i) value of 4.3 micromol x l(-1). Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 micromol x l(-1), whereas higher concentrations of the compound (> 10 micromol x l(-1)) inhibited the hydroxylase activity.


CONCLUSIONS
It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity.
Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, Japan.
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Kudo
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Odomi
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D001712:Biperiden / Q000494:pharmacology; D002354:Carteolol / Q000378:metabolism / Q000494:pharmacology; D002461:Cell Line, Transformed; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology; D013034:Sparteine / Q000494:pharmacology; D014217:Troleandomycin / Q000008:administration & dosage / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D000978:Antiparkinson Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D001712:Biperiden; D013034:Sparteine; D002354:Carteolol; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D006220:Haloperidol