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Open AccessJournal ArticleDOI

Oxidative polymorphism of debrisoquine in Parkinson's disease.

TLDR
A negative correlation was found between MR of DBQ and age at onset of disease in patients free of drugs known to interact with DBQ metabolism, which could be a genetic factor that delays the clinical onset of Parkinson's disease in predisposed people.
Abstract
Oxidative phenotype and metabolic ratio (MR) of debrisoquine (DBQ) have been determined in 87 patients with Parkinson's disease and in 556 healthy control subjects. Three patients (3.45%) and 34 control subjects (6.12%), having an MR greater than 12.6, were classified as poor metabolisers (PM) of DBQ (ns). The distribution of MR values in the 84 Parkinsonian patients classified as extensive metabolisers (EM) showed a less efficient oxidative rate when compared with controls of the same phenotype (p less than 0.001). This difference may be due to enzymatic inhibition caused by drug treatment in 40 of these patients. As in patients not taking any drug known to inhibit the oxidation of DBQ, distribution of MR values was not different from that in controls. A negative correlation (r = -0.36, p less than 0.02) was found between MR of DBQ and age at onset of disease in patients free of drugs known to interact with DBQ metabolism. A higher rate of DBQ oxidation could be a genetic factor that delays the clinical onset of Parkinson's disease in predisposed people.

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Citations
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Journal ArticleDOI

Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease

TL;DR: Determination of CYP2D6 phenotype and genotype may help to identify those at greatest risk of Parkinson's disease and may also help to identified the environmental or metabolic agents involved in the pathogenesis of this disease.
Journal ArticleDOI

Mutant debrisoquine hydroxylation genes in Parkinson's disease

TL;DR: The frequency of fifteen genotypes of CYP2D6 (debrisoquine 4-hydroxylase) in 53 patients with Parkinson's disease was determined by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses and compared with the findings in 72 healthy controls.
Journal ArticleDOI

Increased iron in the substantia-nigra compacta of the mptp-lesioned hemiparkinsonian african-green monkey - evidence from proton microprobe elemental microanalysis

TL;DR: Iron was found not only in the degenerating dopamine cells themselves but also in the surrounding matrix and glial cells and whether free iron that is not bound to neuromelanin is responsible for dopamine cell death as suggested by these experiments remains to be proved.
Journal ArticleDOI

Epidemiologic approaches to the study of Parkinson's disease etiology.

TL;DR: This review evaluates recent evidence concerning the etiology of Parkinson's disease, with emphasis on environmental and lifestyle exposures and their potential interactions with genetic susceptibility traits, and concludes with recommendations for future research directions.
Journal ArticleDOI

P450 enzymes and Parkinson's disease: the story so far.

TL;DR: There is no conclusive evidence to suggest that CYP2D6 polymorphisms confer susceptibility to Parkinson's disease, and polymorphisms in other P450s (for example, CYP1A1 and CYp2E1) are implicated in PD.
References
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Journal ArticleDOI

Parkinsonism: Onset, progression, and mortality

TL;DR: Controversy over the effectiveness of therapeutic measures for parkinsonism is due partially to this wide variability and to the paucity of clinical information about the natural history of the syndrome.
Journal ArticleDOI

Polymorphic hydroxylation of debrisoquine in man

TL;DR: Family studies supported the view that alicyclic 4-hydroxylation of debrisoquine is controlled by a single autosomal gene and that a defect in this metabolic step is caused by a recessive allele.
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Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase.

TL;DR: The neurotoxic chemical MPTP is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min, and the major metabolite has been identified as the 1-methyl-4- phenylpyridinium species.
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Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism.

TL;DR: It is reported here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally and demonstrated that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, indicating that the oxidative metabolism is required for its neurotoxic effect.
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Characterization of the common genetic defect in humans deficient in debrisoquine metabolism.

TL;DR: It is shown that poor meta-bolizers have negligible amounts of the cytochrome P450 enzyme P450dbl, providing a molecular explanation for one of man's most commonly defective genes.
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