P450 phenotyping of the metabolism of selegiline to desmethylselegiline and methamphetamine.
Although there is evidence in the literature of the participation of CYP2B6 in the metabolism of selegiline, it is not clear which other CYP isoforms contribute to its metabolism. The aim of this study was to investigate the P450 isozymes (CYPs) involved in the metabolism of selegiline to desmethylselegiline (DMS) and methamphetamine (MA) using four assays: incubation of selegiline with cDNA expressed CYPs, inhibition of DMS and MA formations in human liver microsomes by CYP-selective chemical inhibitors or CYP-specific antibodies, and correlation analysis. Correlation analysis, performed in a bank of 15 individual human liver microsomes, yielded correlation coefficients for DMS and MA formation of 0.769 and 0.792, respectively, for CYP2B6 (p<0.0001) and 0.333 and 0.349, respectively, for CYP3A4 (p<0.05). These results were supported by chemical/specific antibody inhibition assays. The results of correlation analysis and chemical inhibition also indicated that CYP2A6 seems to play a small role in the metabolism of selegiline. These findings confirm that CYP2B6 plays a major role in the metabolism of selegiline and also suggest the involvement of CYP3A4 and CYP2A6.
Benetton
Salete A
SA
Valeant Research & Development, Costa Mesa, CA 92626, USA.
Fang
Che
C
Yang
Yan-ou
YO
Alok
Ramya
R
Year
Mey
M
Lin
Chin-Chung
CC
Yeh
Li-Tain
LT
D000662:Amphetamines / Q000378:metabolism*; D000911:Antibodies, Monoclonal; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008694:Methamphetamine / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D012642:Selegiline / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
D000662:Amphetamines; D000911:Antibodies, Monoclonal; D065607:Cytochrome P-450 Enzyme Inhibitors; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; D012642:Selegiline; D008694:Methamphetamine; C017861:desmethylselegiline; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating