Coordinated intrahepatic and extrahepatic regulation of cytochrome p4502D6 in healthy subjects and in patients after liver transplantation
| Autor: | Robert A. Branch, Joseph A. Carcillo, Marjorie Romkes, Kenneth E. Thummel, John W. Wilson, Reginald F. Frye, Adedayo Adedoyin, Zourab Bebia, Gilbert J. Burckart, Carmela Knoll, Lorin Roskos, Raman Venkataramanan, Susan Sereika |
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| Rok vydání: | 2003 |
| Předmět: |
Adult
Male CYP2D6 medicine.medical_specialty Genotype medicine.medical_treatment Adrenergic beta-Antagonists Debrisoquin Liver transplantation Biology In Vitro Techniques Hydroxylation digestive system Peripheral blood mononuclear cell Gene Expression Regulation Enzymologic Monocytes chemistry.chemical_compound Adrenergic Agents Reference Values Internal medicine medicine Humans Pharmacology (medical) RNA Messenger Aged Pharmacology Aged 80 and over Reverse Transcriptase Polymerase Chain Reaction Bufuralol Middle Aged Actins Liver Transplantation Transplantation Endocrinology Phenotype Debrisoquine chemistry Cytochrome P-450 CYP2D6 Liver Ethanolamines Microsomes Liver Electrophoresis Polyacrylamide Gel Female Liver function |
| Zdroj: | Clinical pharmacology and therapeutics. 73(5) |
| ISSN: | 0009-9236 |
| Popis: | Cytochrome P450 (CYP) 2D6 activity exhibits wide intersubject variation even among individuals with similar genotypes in whom the active enzyme is expressed. There is, therefore, a need to understand the mechanisms involved in determining its activity. The relationship of messenger ribonucleic acid (mRNA) expression to CYP2D6 activity has been evaluated in hepatic and extrahepatic tissues to test the hypothesis of coordinated regulation. In human liver microsomes, there was a greater than 25-fold variation in both bufuralol hydroxylation and concentration of mRNA for CYP2D6, with a significant association between variables (n = 20; Spearman correlation coefficient [rs] = 0.85, P < .001). In normal subjects, there was a similar extent of interindividual variation in in vivo activity of CYP2D6, measured as the debrisoquin (INN, debrisoquine) recovery ratio, and in mRNA for CYP2D6 in peripheral blood mononuclear cells, with a significant association between variables (n = 78; rs = 0.56 [95% confidence interval, 0.35 to 0.73],P < .001), whereas no association was found between mRNA for CYP2D6 and CYP2E1 activity. Recipients of liver transplants, at a time of stable liver function, had a similar relationship between debrisoquin recovery ratio and concentration of mRNA for CYP2D6 in peripheral blood mononuclear cells (n = 27; rs = 0.74 [95% confidence interval, −0.16 to 0.44], P < .001). Three recipients, who had CYP2D6*4/*4 genotypes, remained phenotypically poor metabolizers for CYP2D6 after liver transplantation. Collectively, these results imply that transcriptional regulation of mRNA for CYP is a major determinant of in vivo activity and that regulation of intrahepatic and extrahepatic enzymes is coordinated, possibly through a mechanism that is predominantly extrahepatic. Clinical Pharmacology & Therapeutics (2003) 73, 456–467; doi: 10.1016/S0009-9236(03)00055-9 |
| Databáze: | OpenAIRE |
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