TY - JOUR
T1 - Substrate specific metabolism by polymorphic cytochrome P450 2D6 alleles
AU - Bogni, Alessia
AU - Monshouwer, Mario
AU - Moscone, Anna
AU - Hidestrand, Mats
AU - Ingelman-Sundberg, Magnus
AU - Hartung, Thomas
AU - Coecke, Sandra
N1 - Funding Information:
Rec27/0110 and Rec15/2739 were kindly supplied by Recordati SpA (Milano, Italy). V79 cells were received from Professor Johannes Doehmer and the Technische Universität München under ECVAM contract 135908-97-12F1ED ISP D “Performance evaluation of an in vitro cytochrome P450 mediated toxicity screening system in view of the prevalidation phase”. This study was supported by EU grant No 17706-2001-03P1B20ISP IT (S.C.) and the Swedish Research Council.
PY - 2005/8
Y1 - 2005/8
N2 - 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.
AB - 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.
KW - Cytochrome P450 2D6
KW - Haloperidol
KW - In vitro
KW - Polymorphism
KW - V79 Chinese hamster cells
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U2 - 10.1016/j.tiv.2005.04.001
DO - 10.1016/j.tiv.2005.04.001
M3 - Article
C2 - 15893449
AN - SCOPUS:19344367709
SN - 0887-2333
VL - 19
SP - 621
EP - 629
JO - Toxicology in Vitro
JF - Toxicology in Vitro
IS - 5
ER -