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Titolo:
Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6
Autore:
Raimundo, S; Fischer, R; Eichelbaum, M; Griese, EU; Schwab, M; Zanger, UM;
Indirizzi:
Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, GermanyDr Margarete Fischer Bosch Inst Clin Pharmacol Stuttgart Germany D-70376
Titolo Testata:
PHARMACOGENETICS
fascicolo: 7, volume: 10, anno: 2000,
pagine: 577 - 581
SICI:
0960-314X(200010)10:7<577:EOTGBO>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPARTEINE METABOLISM; DEBRISOQUINE; POLYMORPHISM; POPULATION; CONSEQUENCES; FREQUENCIES; ALLELES; LOCUS;
Keywords:
CYP2D6; debrisoquine/sparteine polymorphism; intermediate metabolizer; promoter mutation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
18
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:
S. Raimundo et al., "Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6", PHARMACOGEN, 10(7), 2000, pp. 577-581

Abstract

A subgroup of 10-15% of Caucasians are termed phenotypical 'intermediate metabolizers' of drug substrates of CYP2D6 because they have severely impaired yet residual in-vivo function of this cytochrome P450, Genotyping based on the currently known CYP2D6 alleles does not predict this phenotype satisfactorily, A systematic sequencing strategy through 1.6 kb of the CYP2D6 5'-flanking sequence revealed six mutations of which three were exclusively associated with the functional CYP2D6*2 allele (-1496 C to G; -652 C to T; and -590 G to A), two were associated with the nonfunctional *4 and with thefunctional *10-alleles (-1338 C to T and -912 G to A) and one (-1147 A to G) was seen in all *2, *4 and *10-alleles investigated. The -1496 C to G mutation was found to be polymorphic within CYP2D6*2 alleles, In a family study, the wild-type CYP2D6 *2[-1496 C] and the novel variant [-1496 G] alleleco-segregated with lower and higher CYP2D6 in-vivo function, respectively,as shown by phenotyping using sparteine as probe drug, In a representativepopulation sample selected for genotypes comprising one CYP2D6*2 and one non-functional allele, the median urinary metabolic ratio (MR,) for sparteine oxidation was 4.4-fold reduced in individuals with the variant allele (*2[-1496 G], MRs = 0.53, n = 27) compared with individuals lacking the mutation (*2[-1496 C], MRs = 2.33, n=12; P<0.0001). The mutation -1496 C to G hasan estimated frequency of approximately 20% in the general population and allows establishment of a genotype for the identification of over 60% of intermediate metabolizers in Caucasian populations, Pharmacogenetics 10:577-581 (C) 2000 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 22:17:24