Coordinated intrahepatic and extrahepatic regulation of cytochrome p4502D6 in healthy subjects and in patients after liver transplantation.
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 [r(s)] = 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; r(s) = 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; r(s) = 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.
Carcillo
Joseph A
JA
Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Adedoyin
Adedayo
A
Burckart
Gilbert J
GJ
Frye
Reginald F
RF
Venkataramanan
Raman
R
Knoll
Carmela
C
Thummel
Kenneth
K
Roskos
Lorin
L
Wilson
John W
JW
Sereika
Susan
S
Romkes
Marjorie
M
Bebia
Zourab
Z
Branch
Robert A
RA
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D018663:Adrenergic Agents; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis* / Q000235:genetics; D003647:Debrisoquin; D004591:Electrophoresis, Polyacrylamide Gel; D004983:Ethanolamines / Q000493:pharmacokinetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology* / Q000502:physiology*; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000199:Actins; D018663:Adrenergic Agents; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D012333:RNA, Messenger; C010831:bufuralol; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin