DEBRISOQUINE OXIDATION POLYMORPHISM - PHENOTYPIC CONSEQUENCES OF A 3-BASE-PAIR DELETION IN EXON 5 OF THE CYP2D6 GENE

被引:63
作者
BROLY, F [1 ]
MEYER, UA [1 ]
机构
[1] UNIV BASEL,BIOCTR,DEPT PHARMACOL,CH-4056 BASEL,SWITZERLAND
来源
PHARMACOGENETICS | 1993年 / 3卷 / 03期
关键词
D O I
10.1097/00008571-199306000-00001
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
A mutant allele of the CYP2D6 gene (CYP2D6* C) characterized by a 3-base-pair deletion in exon 5 (mutation D6-C) and carried by a Xba I 29 kb restriction fragment (haplotype 29-C) was previously presumed to be associated with the debrisoquine poor metabolizer phenotype on the basis of in vitro enzymatic criteria. In order to determine whether D6-C was related to a deficient CYP2D6 activity in vivo, we first analysed the CYP2D6 gene in the family of a carrier of the haplotype 29-C by combining Xba I-restriction-fragment-length polymorphism analysis and specific CYP2D6 mutation detection by polymerase chain reaction assays. Moreover, each member of the family was phenotyped using debrisoquine as probe drug. Secondly, we used polymerase chain reaction assays to test for the CYP2D 6* C mutation DNA samples from 146 unrelated healthy volunteers with the extensive metabolizer phenotype and previously identified as heterozygous carrier of one of the haplotypes known to be associated with the poor metabolizer phenotype. All family members were extensive metabolizers and three were compound heterozygotes for the haplotype 2 9-C and a 11.5 kb haplotype that has been shown to lack the entire CYP2D6 gene. In addition, two extensive metabolizer individuals among the 146 tested for were compound heterozygotes for the haplotype 29-C and a 29 kb haplotype carrying the defective CYP2D6* B allele (haplotype 29-B). These data demonstrate that in vivo the mutation D6-C does not result in an enzyme deficiency severe enough to cause the poor metabolizer phenotype, in contrast to previous expectations resulting from in vitro data. However, the possibility of a deficiency of the mutant CYP2D6* C protein towards other CYP2D6 substrates cannot be ruled out.
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页码:123 / 130
页数:8
相关论文
共 30 条
  • [21] DETERMINATION OF DEBRISOQUINE AND ITS 4-HYDROXY METABOLITE IN BIOLOGICAL-FLUIDS BY GAS-CHROMATOGRAPHY WITH FLAME-IONIZATION AND NITROGEN-SELECTIVE DETECTION
    LENNARD, MS
    SILAS, JH
    SMITH, AJ
    TUCKER, GT
    [J]. JOURNAL OF CHROMATOGRAPHY, 1977, 133 (01): : 161 - 166
  • [22] POLYMORPHIC HYDROXYLATION OF DEBRISOQUINE IN MAN
    MAHGOUB, A
    IDLE, JR
    DRING, LG
    LANCASTER, R
    SMITH, RL
    [J]. LANCET, 1977, 2 (8038) : 584 - 586
  • [23] MATSUNAGA E, 1990, J BIOL CHEM, V265, P17197
  • [24] MEYER UA, 1989, ADV DRUG RES, V19, P197
  • [25] THE P450 SUPERFAMILY - UPDATE ON NEW SEQUENCES, GENE-MAPPING, AND RECOMMENDED NOMENCLATURE
    NEBERT, DW
    NELSON, DR
    COON, MJ
    ESTABROOK, RW
    FEYEREISEN, R
    FUJIIKURIYAMA, Y
    GONZALEZ, FJ
    GUENGERICH, FP
    GUNSALUS, IC
    JOHNSON, EF
    LOPER, JC
    SATO, R
    WATERMAN, MR
    WAXMAN, DJ
    [J]. DNA AND CELL BIOLOGY, 1991, 10 (01) : 1 - 14
  • [26] NEBERT DW, 1991, CANCER CELL-MON REV, V3, P93
  • [27] A ROUTINE METHOD FOR THE ESTABLISHMENT OF PERMANENT GROWING LYMPHOBLASTOID CELL-LINES
    NEITZEL, H
    [J]. HUMAN GENETICS, 1986, 73 (04) : 320 - 326
  • [28] CODEINE INCREASES PAIN THRESHOLDS TO COPPER VAPOR LASER STIMULI IN EXTENSIVE BUT NOT POOR METABOLIZERS OF SPARTEINE
    SINDRUP, SH
    BROSEN, K
    BJERRING, P
    ARENDTNIELSEN, L
    LARSEN, U
    ANGELO, HR
    GRAM, LF
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1990, 48 (06) : 686 - 693
  • [29] 2 MUTANT ALLELES OF THE HUMAN CYTOCHROME-P-450DB1 GENE (P450C2D1) ASSOCIATED WITH GENETICALLY DEFICIENT METABOLISM OF DEBRISOQUINE AND OTHER DRUGS
    SKODA, RC
    GONZALEZ, FJ
    DEMIERRE, A
    MEYER, UA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (14) : 5240 - 5243
  • [30] IDENTIFICATION OF A NEW VARIANT CYP2D6 ALLELE LACKING THE CODON ENCODING LYS-281 - POSSIBLE ASSOCIATION WITH THE POOR METABOLIZER PHENOTYPE
    TYNDALE, R
    AOYAMA, T
    BROLY, F
    MATSUNAGA, T
    INABA, T
    KALOW, W
    GELBOIN, HV
    MEYER, UA
    GONZALEZ, FJ
    [J]. PHARMACOGENETICS, 1991, 1 (01): : 26 - 32