Differential foetal development of the O- and N-demethylation of codeine and dextromethorphan in man.
1. Codeine and dextromethorphan were N-demethylated in human foetal liver microsomes at high rates which were close to the activities in adult livers. In contrast, foetal liver microsomes did not catalyze the O-demethylation of these drugs at mid-gestation. 2. The metabolic data were in accordance with the absence of P450IID6 and the presence of P450 IIIA as determined by Western blotting with anti-human P450 IID6 (MAb 114/2) and anti-rat P450 IIIA (PCN 2-13-1/C2) monoclonal antibodies, respectively. 3. The inhibitory effects of midazolam and dehydroepiandrosterone support the contention that the N-demethylase is a human foetal form of the cytochrome P450 IIIA family. Consistent with this we found that blotting with the MAb PCN 2-13-1/C2, which recognizes an epitope specific for the P450 III family, correlated well with the N-demethylase activities.
Ladona
M G
MG
Division of Clinical Pharmacology, Academic Hospital, Uppsala, Sweden.
Lindström
B
B
Thyr
C
C
Dun-Ren
P
P
Rane
A
A
D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003061:Codeine / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D003915:Dextromethorphan / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D006801:Humans; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008874:Midazolam / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D003687:Dehydroepiandrosterone; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D008874:Midazolam; D003061:Codeine