Sparteine metabolism capacity in human liver: structural variants of human P450IID6 as assessed by immunochemistry.
An antibody raised against rat P450dbl was used to examine the heterogeneity of the human enzyme involved in the sparteine/debrisoquine polymorphism. The extent to which the antibody was able to inhibit sparteine metabolism varied in different human livers (10-80%, n = 9) and reflected the amount of sparteine metabolism carried out by the polymorphic P450IID6 in individual liver specimens. The individual sample variation in inhibition by the antibody correlated with the inhibition caused by quinidine, a prototype competitive inhibitor of the P450IID6 enzyme active site. Western immunoblots of the liver microsomes confirmed that the variation in the inhibition of sparteine metabolism by this antibody reflected the amount of P450IID6 protein. In addition, a detailed study of one of the livers (K19) which demonstrated a lack of inhibition by the antibody was performed which confirmed the lack of P450IID6 in this liver specimen and suggested that the nascent sparteine metabolism activity was due to other forms of P450.
Department of Pharmacology, Faculty of Medicine, University of Toronto, Ontario, Canada.
R F
RF
Tyndale
F J
FJ
Gonzalez
J P
JP
Hardwick
W
W
Kalow
T
T
Inaba
D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D006801:Humans; D007120:Immunochemistry; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013034:Sparteine / Q000378:metabolism*
D004983:Ethanolamines; D013034:Sparteine; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D011802:Quinidine; D003647:Debrisoquin