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Role of P450IID6, the target of the sparteine‐debrisoquin oxidation polymorphism, in the metabolism of imipramine
Author(s) -
Brøsen Kim,
Zeugin Tanja,
Meyer Urs A
Publication year - 1991
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1991.77
Subject(s) - sparteine , imipramine , metabolism , debrisoquine , pharmacology , polymorphism (computer science) , chemistry , medicine , biology , endocrinology , genetics , cyp2d6 , stereochemistry , gene , allele , cytochrome p450 , alternative medicine , pathology
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 (k i ≈ 70 nmol/L, and k i ≈ 1 µmol/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. Clinical Pharmacology and Therapeutics (1991) 49 , 609–617; doi: 10.1038/clpt.1991.77