Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes

Daly, Ann K.; Armstrong, Martin; Monkman, S. C.; Idle, Morag E.; Idle, Jeffrey R.

doi:10.1097/00008571-199110000-00006

Cited by 86 publications

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“…Although a number of genetic factors have been proposed to explain such differences, results obtained thus far have proven to be weak or limited to specific geographical areas. 4,5,30,31 Four CYP2D6 alleles (CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6) are known to account for 93% to 97% of PM cases, 7 with CYP2D6*4 alone accounting for approximately 75% of these 10,32 ; this is the most widely studied allele in association studies. Brown et al 8 demonstrated a link between the CYP2D6*4 allele and ankylosing spondylitis and postulated that the poor metabolism of xenobiotics by a defective CYP2D6 polymorphism might explain this association.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis

et al. 2004

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Epidemiological data suggest that environmental factors may trigger autoimmunity in genetically susceptible individuals. In primary biliary cirrhosis (PBC), it has been postulated that halogenated xenobiotics can modify self-molecules, facilitating the breakdown of tolerance to mitochondrial antigens. The transport and metabolism of xenobiotics is highly dependent on key genetic polymorphisms that alter enzymatic phenotype. We analyzed genomic DNA from 169 patients with PBC and 225 geographically and sex-matched healthy subjects for polymorphisms of genes coding for cytochromes P450 (CYPs) 2D6 (CYP2D6*4, CYP2D6*3, CYP2D6*5, and CYP2D6*6) and 2E1 (c1/c2), multidrug resistance 1 (MDR1 C3435T) P-glycoprotein, and pregnane X receptor (PXR C-25385T, C8055T, and A7635G). We compared the genotype frequencies in patients and controls and also correlated polymorphisms with PBC severity. The distributions of the studied genotypes did not significantly differ between patients and controls. However, when clinical characteristics of patients with PBC were compared according to genotype, the CYP2E1 c2 allele was associated with signs of more severe disease. In conclusion, genetic polymorphisms of CYP 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of PBC. (HEPATOLOGY 2005;41:55-63.)

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis

et al. 2004

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“…However, it had been observed at the outset (Mahgoub et al, 1977) that the two phenotypes EM and PM harbored a wide range of metabolic capacity, suggesting variables other than the CYP2D6 genotype might be operating to determine an individual's capacity to 4-hydroxylate a test dose of debrisoquine. Daly et al (1991), making a population-based phenotype-genotype correlation, showed that genotypic EMs could have metabolic ratio values from 0.1 to 8, corresponding to 11 to 91% metabolism of debrisoquine; even heterozygotes alone metabolized from 11 to 77% of the administered debrisoquine. In addition to this 7-fold range of metabolism of debrisoquine within a genotypically homogeneous group, one further anomaly, ob-served in this and other studies, is the residual metabolism (up to 7% of the dose) of debrisoquine in the PM phenotype.…”

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confidence: 99%

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Granvil

Krausz²,

Gelboin³

et al. 2002

J Pharmacol Exp Ther

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A panel of 15 recombinant cytochromes P450 expressed in human B-lymphoblastoid cells was used to study debrisoquine 4-hydroxylation. Both CYP2D6 and CYP1A1 carried out the reaction. The apparent K m (micromolar) and V max (picomoles per minute per picomole of P450) for CYP2D6 were 12.1 and 18.2 and for CYP1A1 were 23.1 and 15.2, respectively. CYP1A1 debrisoquine 4-hydroxylase was inhibited by the CYP1A1 inhibitor ␣-naphthoflavone and the CYP1A1 substrate 7-ethoxyresorufin. Additionally and surprisingly, this reaction was also inhibited by quinidine and quinine, with respective IC 50 values of 1.38 Ϯ 0.10 and 3.31 Ϯ 0.14 M, compared with those for CYP2D6 debrisoquine 4-hydroxylase of 0.018 Ϯ 0.05 and 3.75 Ϯ 2.07 M, respectively. Anti-CYP1A1 monoclonal antibody (mAb) 1-7-1 abolished CYP1A1 debrisoquine hydroxylase and anti-CYP2D6 mAb 50-1-3 eradicated CYP2D6 debrisoquine 4-hydroxylase. Three further CYP2D6-specific reactions were tested: dextromethorphan O-demethylation, bufuralol 1Ј-hydroxylation, and sparteine dehydrogenation. The CYP2D6 specificity, judged by the CYP2D6/CYP1A1 activity ratios was 18.5, 7.0, 6.0, and 1.6 for dextromethorphan, bufuralol, sparteine, and debrisoquine, respectively. Thus, debrisoquine is not a specific CYP2D6 substrate and quinidine is not a specific CYP2D6 inhibitor. These findings have significant implications for the conduct of in vitro drug metabolism inhibition studies and underscore the fallacy of "specific chemical inhibitors" of a supergene family of enzymes that have overlapping substrate specificities. The use of highly specific mAbs in such studies is mandated. It is unclear as yet whether these findings have implications for the relationship between CYP2D6 genotype and in vivo debrisoquine 4-hydroxylase activity.

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“…However the CYP2D7 gene (located between the CYP2D8P and CYP2D6 genes) has a similar structure to that of the functional CYP2D6 gene, except for a characteristic single reading frame-disrupting insertion (T226) in its first exon. It has been hypothesised that both gene conversions and unequal crossing-overs within this family of tandemly repeated genes could account for its high degree of polymorphism in man. To date, only five variant CYP2D6 alleles namely, D6A, D6B, D6D, phenotype data [16]. In this study, we report the molecular characterization of a novel PM allele.…”

Section: Introductionmentioning

confidence: 92%

An unequal cross‐over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

Panserat

Mura

Gérard

et al. 1995

Brit J Clinical Pharma

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1. The study of the CYP2D genotype and phenotype of a Caucasian family revealed that a XbaI‐9 kb allele was associated with the poor metabolizer phenotype. 2. A Polymerase Chain Reaction (PCR)‐based assay showed that the previously described mutations D6A and D6B are not associated with the XbaI‐9 kb allele. 3. To explore the molecular basis of the poor metabolizer phenotype associated with the XbaI‐9 kb allele, complete sequencing of the nine exons and intron‐exon boundaries of the CYP2D6 gene was undertaken after amplification by PCR. 4. All the exons were successfully amplified using CYP2D6 gene‐specific primers except exon 1 which required a combination of CYP2D7 gene‐specific 5' primer and a CYP2D6 gene‐specific 3' primer. 5. Sequence data derived from this amplified product revealed that the XbaI‐9 kb allele corresponds to a novel rearrangement of the locus. This involved a deletion of an approximately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2D6 3' gene. 6. The chimeric gene is non‐functional presumably due to an insertion in exon 1 (characteristic of the exon 1 of the CYP2D7 gene) which causes a shift in the reading frame with premature termination of translation.

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Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes

Cited by 86 publications

References 0 publications

Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis

Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

An unequal cross‐over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

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