Substrate specific metabolism by polymorphic cytochrome P450 2D6 alleles.
A comparative metabolism study was performed for bufuralol, dextromethorphan, imipramine, mianserin, sparteine, tamoxifen, haloperidol and two drug candidates (Rec27/0110 and Rec15/2739) on V79 cells genetically engineered to express human cytochrome P450 (CYP) variants 2D6*1, 2D*2, 2D*9 and 2D*17. Unexpectedly, the CYP2D6*17 dependent metabolism profile of haloperidol and Rec27/0110 were found to differ from all other substrates tested. Some of these known standard substrates are frequently applied in marker reactions for CYP2D6 and with these standard substrates, CYP2D6*1 is known to be the most active form. In both cases of haloperidol and Rec27/0110 the variant form CYP2D6*17 had equal or higher activity compared to the CYP2D6*1 form. Results obtained with the V79 cells were confirmed using microsomal preparation of yeast cells expressing the variants CYP2D6*1 and CYP2D6*17 and CYP2D6 inhibitor quinidine. In conclusion, there is no general rule for a variant dependent metabolism profile by cytochrome P450 2D6 indicating that the activity profile of the CYP2D6 alleles may be substrate specific, thus may be reflected in pharmacokinetics consequences for individuals.
Bogni
Alessia
A
ECVAM, Institute for Health & Consumer Protection, Joint Research Centre, European Commission, 21020 Ispra, Italy.
Monshouwer
Mario
M
Moscone
Anna
A
Hidestrand
Mats
M
Ingelman-Sundberg
Magnus
M
Hartung
Thomas
T
Coecke
Sandra
S
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004983:Ethanolamines / Q000493:pharmacokinetics; D006801:Humans; D011110:Polymorphism, Genetic; D013379:Substrate Specificity
D004983:Ethanolamines; C010831:bufuralol; D019389:Cytochrome P-450 CYP2D6