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Titolo:
Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6
Autore:
Zanger, UM; Fischer, J; Raimundo, S; Stuven, T; Evert, BO; Schwab, M; Eichelbaum, M;
Indirizzi:
Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, GermanyDr Margarete Fischer Bosch Inst Clin Pharmacol Stuttgart Germany D-70376 Univ Tubingen, Dept Clin Pharmacol, D-72074 Tubingen, Germany Univ Tubingen Tubingen Germany D-72074 rmacol, D-72074 Tubingen, Germany
Titolo Testata:
PHARMACOGENETICS
fascicolo: 7, volume: 11, anno: 2001,
pagine: 573 - 585
SICI:
0960-314X(200110)11:7<573:CAOTGF>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
POOR METABOLIZER PHENOTYPE; DEBRISOQUINE OXIDATION POLYMORPHISM; POLYMERASE CHAIN-REACTION; SPARTEINE METABOLISM; EUROPEAN POPULATION; DRUG-METABOLISM; ALLELE; DELETION; IDENTIFICATION; HYDROXYLATION;
Keywords:
cytochrome P450; debrisoquine/sparteine polymorphism; intermediate metabolizer; ultrarapid metabolizer;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Zanger, UM Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, D-70376 Stuttgart, Germany Dr Margarete Fischer Bosch Inst Clin PharmacolAuerbachstr 112 Stuttgart Germany D-70376
Citazione:
U.M. Zanger et al., "Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6", PHARMACOGEN, 11(7), 2001, pp. 573-585

Abstract

Variable expression and function of the cytochrome P4502D6 (CYP2D6) leads to distinct phenotypes termed ultrarapid (UM), extensive (EM), intermediate(IM) and poor metabolizer (PM). Whereas the PM phenotype is known to be caused by two null-alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remained largely unexplained. In this study, we systematically investigated 76 liver biopsies from individuals with known sparteine metabolic ratios (MRS) for therelationships between CYP2D6 genotype, microsomal protein expression, bufuralol 1'-hydroxylase activity and in-vivo phenotype. Average CYP2D6 proteinlevels ranged from undetectable in PMs (MRS > 20) to 2.6 +/- 2.7 pmol/mg microsomal protein in IMs (1.2 < MRS< 20), 7.6 +/- 4.7 in EMs (0.2 < MRS < 1.2) and 23.8 +/- 7.7 in UMs (MRS < 0.2), respectively. Analysis with respect to genotype demonstrated gradually increased expression and function for individuals with no, one, two or three functional gene copies per genome. The recently discovered -1584 C/G promoter polymorphism was identified as another major factor for expression and function with the mutant [-1584G] promoter type being consistently associated with significantly higher expression than [-1584C]. To investigate functional differences between the detected variant protein forms CYP2D6.1, 2D6.2, 2D6.9 and 2D6.10, we expressed them recombinantly in insect cells. The most significant difference was a decrease in the relative P450 holoprotein content of all allelic forms, including the common functional variant 2D6.2, in comparison to 2D6.1, whereas only modest K-m changes were observed. Taken together, these data provide further insight into the complex mechanisms that govern the highly variable expression and function of CYP2D6. Pharmacogenetics 11:573-595 (C) 2001 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 14:43:17