In vitro identification of the cytochrome P450 isoform responsible for the metabolism of alpha-dihydroergocryptine.
1. The in vitro metabolism of alpha-dihydroergocryptine (DHEC, Almirid), an ergot-derived dopamine agonist for the treatment of Parkinson's disease, has been studied in cultured cell lines following incubation with DHEC. Human hepatocytes as well as two sets of metabolically competent cell lines expressing one single human cytochrome P450 (1A1, 1A2, 1B1, 2A6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4) were used. 2. Mono- and dihydroxy metabolites of DHEC could only be detected in the culture media of the cell line expressing human cytochrome CYP3A4. The same metabolites were found in the media of cultured human hepatocytes derived from three different donors. After 24-h incubation with 1 microM DHEC, approximately 60% mono- and approximately 20% dihydroxy metabolites were detected, i.e. approximately 80% of DHEC was metabolized. Further, DHEC demonstrated an inhibitory effect on CYP3A4-mediated testosterone metabolism and additionally could induce CYP3A4 and CYP2E1 mRNA when added at 10 microM to cultured human hepatocytes. 3. The data suggest that DHEC metabolism in humans is primarily mediated by the CYP3A4 isoform. The results are in accordance with findings derived from other ergot alkaloids.
Althaus
M
M
Desitin Arzneimittel GmbH, Weg beim Jäger 214, D-22335 Hamburg, Germany. althaus@desitin.de
Retzow
A
A
Castell
J V
JV
Gómez-Lechón
M J
MJ
Amalou
Z
Z
Rose
T
T
Appel
K
K
D000368:Aged; D000818:Animals; D001971:Bromocriptine / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D004088:Dihydroergotoxine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006915:Hydroxytestosterones / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D008956:Models, Chemical; D020033:Protein Isoforms; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D018491:Dopamine Agonists; D006915:Hydroxytestosterones; D020033:Protein Isoforms; D012333:RNA, Messenger; D004088:Dihydroergotoxine; D001971:Bromocriptine; C025591:6 beta-hydroxytestosterone; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human