Poor hydroxylator phenotypes of debrisoquine and S‐mephenytoin are not over‐represented in a group of patients with Parkinson's disease [letter]

Gudjonsson, Olafur; Sanz, Emilio J.; Alván, Gunnar; Sm, Aquilonius; Reviriego, Jesús

doi:10.1111/j.1365-2125.1990.tb03780.x

Cited by 22 publications

(4 citation statements)

References 12 publications

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“…13-*' However, other investigators have not found differences in CYP2D6 phenotype between patients with Parkinson's disease and healthy subjects. [30][31][32][33] Because the mechanism linking CYP2D6 and Parkinson's disease seems to be attributable to the interaction of genetic and environmental factors, the origin of the conflicting reports on CYP2D6 and Parkinson's disease may be attributable to different exposure to toxins in the populations studied. With few exceptions, there is a general agreement in the findings obtained by phenotyping and genotyping studies in most populations.…”

Section: Discussionsupporting

confidence: 93%

Association between the oxidative polymorphism and early onset of Parkinson's disease*

Agúndez

Jiménez‐Jiménez

Luengo

et al. 1995

Clin Pharmacol Ther

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The frequency of five cytochrome P450IID6 allelic variants was studied in deoxyribonucleic acid from 123 patients with Parkinson's disease and 150 healthy volunteers. This was achieved by the use of mutation-specific polymerase chain reaction and restriction fragment length polymorphism. The analyses of the CYP2D6 genotype revealed no evidence for a higher prevalence of poor metabolizers among patients with Parkinson's disease. However, increased frequency of patients with Parkinson's disease with the genotype CYP2D6wt/CYP2D6B was observed. This is attributable exclusively to subjects with early onset of the disease (28 to 49 years), with a relative risk ratio of 4.16 (95% confidence limits, 2.0 to 8.3; p < 0.0005). The subjects who had late-onset Parkinson's disease (> or = 50 years) had genotypes and CYP2D6 allele frequencies similar to the healthy subjects. This indicates that the oxidative polymorphism is related to early-onset but not to late-onset Parkinson's disease. A different influence of CYP2D6 genotype on the risk of development of Parkinson's disease is observed in Spaniards, compared with previous findings in British subjects. These results suggest the combined effect of environmental toxins and CYP2D6 in the cause of Parkinson's disease.

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Section: Discussionsupporting

confidence: 93%

Association between the oxidative polymorphism and early onset of Parkinson's disease*

Agúndez

Jiménez‐Jiménez

Luengo

et al. 1995

Clin Pharmacol Ther

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“…However, CYP450 in particular drew attention, due to its ability to defend the body against xenobiotic aggression. In particular, six P450 enzymes have been examined with respect to PD: CYP 1A1 (Kurth and Kurth, 1993; Bennet et al, 1994; Takakubo et al, 1996), CYP 2C9 (Ferrari et al, 1990; Peeters et al, 1994), CYP 2C19 (Gudjonsson et al, 1990; Tsuneoka et al, 1996), CYP 1A2, CYP 2E1 (Factor et al, 1989; Steventon et al, 1989), and CYP 2D6 (Riedl et al, 1998). Since the first enthusiastic claim, more than 50 reports have debated the role of CYP 2D6 in the pathogenesis of PD.…”

Section: The P450 System In Pdmentioning

confidence: 99%

Acetaldehyde and parkinsonism: role of CYP450 2E1

Vaglini¹,

Viaggi²,

Piro³

et al. 2013

Front. Behav. Neurosci.

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The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.

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“…The phenotypic expression of a component of the cytochrome P 450 system (CYP 2D6) can be assessed by measuring metabolism of the drug debrisoquine. Some researchers have found altered debrisoquine metabolism to be relatively common among PD patients [44,45]; others have not [46,47]. Reexamination of this issue was prompted by the identification of the human gene coding for the P 450 cytochrome oxidase system [48].…”

Section: Discussionmentioning

confidence: 99%

Gene-Toxin Interaction as a Putative Risk Factor for Parkinson’s Disease with Dementia

Hubble

Kurth²,

Glatt³

et al. 1998

Neuroepidemiology

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We had previously examined environmental, sociodemographic and clinical variables as predictors for Parkinson’s disease with dementia (PD + D) and found that lower educational attainment, greater motor impairment and advanced age at disease onset were more common in PD + D than in subjects with Parkinson’s disease without dementia (PD – D). We now explore the hypothesis that genetic traits coupled with nongenetic factors may raise the risk of development of PD + D. The study cohort of 43 PD + D and 51 PD – D subjects was analyzed examining environmental, sociodemographic and clinical variables along with 3 candidate gene markers: poor debrisoquine metabolizer allele (CYP 2D6 29B+), monoamine oxidase B allele 1, and apolipoprotein E ε4 allele. Variables were initially entered into a multivariate model singly. Again lower education, age at onset and motor impairment appeared as predictors of PD + D while other variables (including allele status) failed to emerge as significant individual risk factors for dementia. We then examined environmental and genetic variables analyzed in tandem to look for potential variable interactions. Subjects who had pesticide exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted probability of PD + D (stepwise logistic regression model: p = 0.0491). This case-control study provides preliminary evidence that a gene-toxin interaction may play an etiological role in PD + D. Further assessment of the role of these putative risk factors in incident dementia in PD is indicated.

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Poor hydroxylator phenotypes of debrisoquine and S‐mephenytoin are not over‐represented in a group of patients with Parkinson's disease [letter]

Cited by 22 publications

References 12 publications

Association between the oxidative polymorphism and early onset of Parkinson's disease*

Association between the oxidative polymorphism and early onset of Parkinson's disease*

Acetaldehyde and parkinsonism: role of CYP450 2E1

Gene-Toxin Interaction as a Putative Risk Factor for Parkinson’s Disease with Dementia

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