Perazine as a potent inhibitor of human CYP1A2 but not CYP3A4.
The effects of perazine on the activities of CYP1A2 and CYP3A4 in a primary culture of human hepatocytes of one patient were studied in vitro. The CYPs activities were assessed by measuring the rate of acetanilide 4-hydroxylation (CYP1A2) and cyclosporine A oxidation (CYP3A4) after treatment with TCDD (a CYP1A subfamily inducer) or rifampicin (mainly a CYP3A4 inducer). The amounts of the metabolites formed in hepatocytes were assayed in the extracellular medium using the HPLC method. TCDD and rifampicin induced the formation of 4-hydroxyacetanilide and cyclosporine A metabolites (monohydroxycyclosporine A, dihydroxycyclosporine A, N-desmethylcyclosporine A), respectively. The formation of 4-hydroxyacetanilide was strongly inhibited by three different concentrations of perazine (10, 25 and 50 microM) reaching 8, 3 and 2% of the control value, respectively. In the case of CYP3A4 activity, no such an effect of perazine was observed. Perazine showed only a week inhibition of the activity of cyclosporine A oxidase (to 96-86% of the control value). The obtained results suggest a strong inhibitory effect of perazine on human CYP1A2 activity with predicted Ki value similar to those of the known for CYP1A2 inhibitors, such as furafylline and fluvoxamine.
Wójcikowski
Jacek
J
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. wojcikow@if-pan.krakow.pl
Pichard-Garcia
Lydiane
L
Maurel
Patrick
P
Daniel
Władysława A
WA
D000083:Acetanilides / Q000493:pharmacokinetics; D000368:Aged; D001711:Biotransformation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000493:pharmacokinetics; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D010464:Perazine / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology
D000083:Acetanilides; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D016572:Cyclosporine; D010464:Perazine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human