Role of P450IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine.
The formation of three oxidative metabolites of imipramine, N-desmethylimipramine (desipramine), 2-hydroxyimipramine, and 10-hydroxyimipramine was studied in microsomes of an extensive metabolizer liver (KDL 26) and of a poor metabolizer liver (KDL 31) and in a homogenate of COS-1 cells in which the P450IID6 complementary deoxyribonucleic acid had been expressed. The following data support the role of P450IID6 in the 2-hydroxylation of imipramine: (1) The formation of 2-hydroxyimipramine was reduced to less than 20% of the control value when microsomes were incubated with serum containing inhibitory antibodies against P450IID6 (anti-LKM1), whereas no effect was seen with regard to formation of desipramine and 10-hydroxyimipramine, (2) quinidine and levomepromazine were potent competitive inhibitors of 2-hydroxylation of imipramine (ki approximately 70 nmol/L, and ki approximately 1 mumol/L, respectively) but had no effect on N-demethylation and 10-hydroxylation, and (3) in the COS-1 cell, homogenate, 10-hydroxyimipramine, 2-hydroxyimipramine, and desipramine were formed at rates of 48, 164, and 256 pmol per hour per milligram of homogenate protein, respectively. The P450 isozymes that are responsible for N-demethylation and 10-hydroxylation of imipramine have not yet been identified.
Brøsen
K
K
Biozentrum der Universität, Basel, Switzerland.
Zeugin
T
T
Meyer
U A
UA
D000906:Antibodies / Q000378:metabolism; D002478:Cells, Cultured; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004247:DNA / Q000235:genetics; D003647:Debrisoquin / Q000378:metabolism*; D006801:Humans; D007099:Imipramine / Q000031:analogs & derivatives / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology*; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008728:Methotrimeprazine / Q000494:pharmacology; D008862:Microsomes, Liver / Q000276:immunology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000502:physiology*; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic / Q000502:physiology*; D011802:Quinidine / Q000494:pharmacology; D013034:Sparteine / Q000378:metabolism*; D014162:Transfection
D000906:Antibodies; D007527:Isoenzymes; D013034:Sparteine; C033803:2-hydroxyimipramine; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D008728:Methotrimeprazine; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D007099:Imipramine; D003647:Debrisoquin