RT Journal Article
SR Electronic
T1 Estimation of drug-metabolizing capacity by CYP-genotyping and CYP-expression
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.189597
DO 10.1124/jpet.111.189597
A1 Temesvari, Manna
A1 Kobori, Laszlo
A1 Paulik, Jozsef
A1 Sarvary, Eniko
A1 Belic, Ales
A1 Monostory, Katalin
YR 2012
UL http://jpet.aspetjournals.org/content/early/2012/01/19/jpet.111.189597.abstract
AB Many undesired side-effects or therapeutic failures of drugs are the results of differences or changes in drug-metabolism, primarily depending on the levels and activities of cytochrome P450 (CYP) enzymes. In order to assess whether CYP-expression profiles can reflect the hepatic drug-metabolism, we compared CYP mRNA levels in the liver or in peripheral leukocytes with the corresponding hepatic CYP-activities. A preliminary CYP-genotyping for the most frequent polymorphisms in Caucasian populations (CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, CYP2D6*6 and CYP3A5*3) was carried out before CYP-phenotyping, excluding the donors with non-functional alleles of CYP2C9, CYP2C19 and CYP2D6, and those with functional CYP3A5*1 allele from a correlation analysis. The hepatic mRNA levels of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 displayed a strong association with CYP-activities in the liver, whereas the expression of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in leukocytes was proven to reflect the hepatic activities of these CYP species. The leukocytes were found to be inappropriate cells for the assessment of hepatic CYP2B6 and CYP2D6 activities. Combining the results of CYP-genotyping and CYP-phenotyping analyses, patients' drug-metabolizing capacities can be estimated by the CYP-expression in the liver and also in leukocytes, with some limitations. Patients' genetic and non-genetic variations in CYP-status can guide the appropriate selection of drugs and the optimal dose, minimizing the risk of harmful side-effects and ensuring a successful outcome of drug therapy.