Cytochrome P450IID subfamily in non-human primates. Catalytical and immunological characterization.
Interindividual variations of debrisoquine metabolism was recently identified in non-human primates tested in vivo. The catalytical and immunological characterization of cytochrome P450IID subfamily was undertaken in hepatic microsomes from extensive metabolizer primates. The NADPH/O2 mediated metabolism of debrisoquine, dextromethorphan and bufuralol was similar to the kinetics reported in humans. The CuOOH mediated metabolism of bufuralol suggested that at least two enzymes are responsible for bufuralol 1'-hydroxylation. Eleven compounds were tested for their capacity to modify P450IID function in vitro. Eight competitive inhibitors of P450IID6 in man were all and exclusively competitive inhibitor of P450IID subfamily in non-human primates. Quinidine, which is the strongest competitive inhibitor in man, exhibited the higher inhibitory potency in monkey (Ki = 0.75 microM). Anti-LKM antibody against P450IID subfamily cross-reacted with two proteins of 49 and 47 kDa, and sera containing anti-LKM antibody against these two proteins inhibited dextrorphan formation in vitro. These data provide evidence for catalytical and immunological similarities between human and monkey microsomes and indicate that the primate system could be a model for enzymatic studies of P450IID.
Jacqz-Aigrain
E
E
Unité de Pharmacologie Clinique, Hôpital Robert-Debre, Paris, France.
Gueguen
M
M
Zanger
U M
UM
Robieux
I
I
Alvarez
F
F
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001667:Binding, Competitive; D003429:Cross Reactions; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism
D001323:Autoantibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D004983:Ethanolamines; D007527:Isoenzymes; C060729:anti-liver kidney microsome antibody; D003915:Dextromethorphan; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; C052861:dextromethorphan O-demethylase; D019389:Cytochrome P-450 CYP2D6; C043872:bufuralol 1'-hydroxylase; D003647:Debrisoquin