Cytochrome P-450 activities in human and rat brain microsomes.
The role of cytochrome P450 in the metabolism of dextromethorphan, amitriptyline, midazolam, S-mephenytoin, citalopram, fluoxetine and sertraline was investigated in rat and human brain microsomes. Depending on the parameters, the limit of quantification using gas chromatography-mass spectrometry methods was between 1.6 and 20 pmol per incubation, which generally contained 1500 microg protein. Amitriptyline was shown to be demethylated to nortriptyline by both rat and human microsomes. Inhibition studies using ketoconazole, furafylline, sulfaphenazole, omeprazole and quinidine suggested that CYP3A4 is the isoform responsible for this reaction whereas CYP1A2, CYP2C9, CYP2C19 and CYP2D6 do not seem to be involved. This result was confirmed by using a monoclonal antibody against CYP3A4. Dextromethorphan was metabolized to dextrorphan in rat brain microsomes and was inhibited by quinidine and by a polyclonal antibody against CYP2D6. Only the addition of exogenous reductase allowed the measurement of this activity in human brain microsomes. Metabolites of the other substrates could not be detected, possibly due to an insufficiently sensitive method. It is concluded that cytochrome P450 activity in the brain is very low, but that psychotropic drugs could undergo a local cerebral metabolism which could have pharmacological and/or toxicological consequences.
Voirol
P
P
Unité de Biochimie et Psychopharmacologie Clinique, Département Universitaire de Psychiatrie Adulte, CH-1008 Prilly, Lausanne, Switzerland.
Jonzier-Perey
M
M
Porchet
F
F
Reymond
M J
MJ
Janzer
R C
RC
Bouras
C
C
Strobel
H W
HW
Kosel
M
M
Eap
C B
CB
Baumann
P
P
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System