Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease

Smith, Colin; Wolf, C. Roland; Gough, A C; Spurr, N.K.; Leigh, P. Nigel; Summers, BA; Harding, A. E.; Maranganore, D.M; Sturman, S. G.; Williams, Adrian; Schapira, Anthony H.V.

doi:10.1016/0140-6736(92)91196-f

Cited by 387 publications

(177 citation statements)

References 26 publications

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“…We used the PCR method of Smith et al [22], with some modifications, to detect the two most frequent mutations, CYP2D6-A and CYP2D6-B, which are responsible for the poor metaboliser phenotype in greater than 90% of cases. Rarer mutations, which in general occur at a frequency of less than 1%, and deletion of the gene itself which is responsible for the PM mutation in <2% of cases, were not analyzed.…”

Section: Determination Of Cyp2d6 Genotypementioning

confidence: 99%

“…Poor metabolisers attain high plasma concentrations of a variety of psychotropic drugs, including clomipramine, desipramine and nortriptyline, and may experience adverse reactions even on low doses [16]. Mutations of the CYP2D6 gene causing a deficient or absent protein are responsible for the poor metaboliser phenotype and several methods for their detection, including PCR methods, have been described [17][18][19][20][21][22]. Known Clozapine response was determined using the Global Assessment Scale (GAS) [24] before and after clozapine treatment by observers blind to laboratory results using a 20-point improvement in GAS scores as a cutoff point for response.…”

Section: Introductionmentioning

confidence: 99%

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Cytochrome P4502D6 genotype does not determine response to clozapine.

Arranz

Dawson

et al. 1995

Brit J Clinical Pharma

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Section: Determination Of Cyp2d6 Genotypementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytochrome P4502D6 genotype does not determine response to clozapine.

Arranz

Dawson

et al. 1995

Brit J Clinical Pharma

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“…The blood samples were analyzed for two major defective alleles for the CYP2D6 gene -CYP2D6*4 and CYP2D6*3 -by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method according to the procedure proposed by Smith et al [8]. DNA was arranged from leukocytes extracted from peripheral blood.…”

Section: Examination Of Genotype Oxidationmentioning

confidence: 99%

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Wojtczak

Skrętkowicz

2014

Pharmacological Reports

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The currently used b-blockers differ in their selectivity for b 1 -and b 2 -adrenergic receptors, lipophilicity and route of elimination. Metoprolol is one of the most commonly used b-blockers in the treatment of ischemic heart disease. Metoprolol is a lipophilic b 1 -selective blocker. This drug is well absorbed from the gastrointestinal tract and undergoes extensive distribution in body tissues; it also passes through the blood-brain barrier. The highest plasma concentration value of metoprolol is reached approximately 2 h after administration of a single dose. Metoprolol is extensively metabolized (oxidation) in the liver by the CYP2D6 isoenzyme of cytochrome P450 [2].The gene encoding the CYP2D6 enzyme is highly polymorphic. The CYP2D6 oxidation polymorphism has a major impact on the Background:Metoprolol is the one of the most commonly used b-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease. Methods: Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50 mg. The blood samples were analyzed for two major defective alleles for CYP2D6 -CYP2D6*4 and CYP2D6*3 -by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection). Results: In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 AE SD 36.78 ng/ml vs. mean 168.22 AE SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p = 0.0009). Conclusions: This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma.

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“…However, correlation studies using CYP2D6 genotyping, functional assays and western blotting utilised a panel of six characterised human livers. The genotyping procedure, that of Smith et al [16], involved polymerase chain reaction (PCR), followed by restriction digestion of the amplified products with Bst NI and Hpa II. This method is able to detect approximately 95% of mutations which render an individual a phenotypic poor metaboliser of the debrisoquine/sparteine type.…”

Section: Preparation Of Microsomes From Human Liversmentioning

confidence: 99%

An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.

Halliday

Jones

Smith

et al. 1995

Brit J Clinical Pharma

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3 Microsomes prepared from recombinant CYP2D6 and CYP3A4 cell lines were shown to catalyse halofantrine N-debutylation. 4 The metabolism of halofantrine to its N-desbutyl metabolite by human liver microsomes showed no correlation with CYP2D6 genotypic or phenotypic status and there was no consistent inhibition by quinidine. 5 The rate of halofantrine metabolism showed a significant correlation with both CYP3A4 protein levels (r = 0.88, P = 0.01) and the rate of felodipine metabolism (r = 0.86, P = 0.013), a marker substrate for CYP3A4 activity. Inhibition studies showed that ketoconazole is a potent inhibitor of halofantrine metabolism (IC50 =

show abstract

Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease

Cited by 387 publications

References 26 publications

Cytochrome P4502D6 genotype does not determine response to clozapine.

Cytochrome P4502D6 genotype does not determine response to clozapine.

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.

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