Oxidative polymorphism of debrisoquine in Parkinson's disease.

Benı́tez, Julio; Ladero, José M.; Jiménez-Jiménez, F J; Martı́nez, Carmen; Puerto, A M; Valdivielso, María José López de; LLerena, Adrián; Cobaleda, Jesús; Múñoz, Juan José

doi:10.1136/jnnp.53.4.289

Cited by 35 publications

(10 citation statements)

References 29 publications

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“…Their MRs varied between 0.22 and 2.40, and the values were not significantly different from MRs of EM parkinsonians with disease onset at the age of over 48 years (range 0.10-5.50). Also, we did not find any reverse correlation between MR and age at disease onset observed in a recent study (24). Therefore, our findings would not support an earlier hypothesis that an environmental neurotoxin (possibly similar to MPTP or MPP + )metabolized by P-450IID6 would cause Parkinson's disease at younger age in PMs, who would be unable to inactivate the compound It has been shown earlier that debrisoquine MR is independent of age or renal clearance of the drug (25)(26).…”

Section: Discussioncontrasting

confidence: 68%

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Debrisoquine oxidation in Parkinson's disease

Kallio

Marttila

Rinne

et al. 1991

Acta Neurologica Scandinavica

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Variations in the activities of xenobiotic metabolizing liver enzymes may be involved in the pathophysiology of diseases, including Parkinson's disease. We therefore studied the activity of the debrisoquine metabolizing enzyme in 97 patients with newly diagnosed Parkinson's disease. The urine debrisoquine metabolic ratios (MR) of the patients were compared with a group of 176 healthy subjects. There were 4 poor metabolizers (4.1%) among the parkinsonians. This proportion did not differ from that found in the group of healthy subjects (51%). In contrast to earlier finding, the parkinsonian poor metabolizers (PM) had the onset of the disease later than the parkinsonian extensive metabolizers (EM). In the parkinsonian patients, it was observed that the excretion of debrisoquine and 4-OH-debrisoquine into urine correlated inversely with the actual age and age at disease onset. Our results indicate that in patients with Parkinson's disease, debrisoquine hydroxylation is comparable with healthy subjects.

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Section: Discussioncontrasting

confidence: 68%

“…The results are in accordance with some earlier studies (21)(22). Also, we did not find any reverse correlation between MR and age at disease onset observed in a recent study (24). In our study, all 4 PMs with Parkinson's disease had disease onset at older age than the EMS.…”

Section: Discussioncontrasting

confidence: 63%

Debrisoquine oxidation in Parkinson's disease

Kallio

Marttila

Rinne

et al. 1991

Acta Neurologica Scandinavica

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“…An initial report by Barbeau et al4" showed a statistically significantly higher number of CYP2D6 PMs in PD patients than in control subjects. This study was flawed because it included PD patients who were taking orphenadrine, which is a substrate of CYP2D6 and thus interferes with the a~s a y .~' Similarly, Benitez et al 42 found a significant correlation between PD and PM phenotypes, but the difference was not statistically significant when the analysis was narrowed to the untreated patients (n = 45). The most comprehensive study was that of Steventon et al,43 who compared drug-naive PD patients with age-matched control subjects and found no difference.…”

Section: Cyp2d6 Pms and Pdmentioning

confidence: 99%

P450 enzymes and Parkinson's disease: The story so far

et al. 1998

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Environmental or endogenous toxins may cause nigral cell death in Parkinson's disease (PD) as a result of genetic susceptibility conferred by altered expression of P450 enzymes. Attention over the last 10 years has focused on CYP2D6 polymorphisms and susceptibility to PD. This review summarizes reports arising from both phenotypic and genotypic studies involving CYP2D6 and PD. Phenotypic studies have failed to support a link between CYP2D6 and PD. The more powerful genetic studies initially indicated a link between CYP2D6B mutations and PD, but critical analysis of the literature and recent studies emerging from independent laboratories fail to confirm this. Mutations in CYP2D6B are also not implicated in familial PD. As yet, there is no conclusive evidence to suggest that CYP2D6 polymorphisms confer susceptibility to PD. Whether polymorphisms in other P450s (for example, CYP1A1 and CYP2E1) are implicated in PD remains to be established.

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“…[13][14][15][16][17][18][19][20][21][22] Several studies indicate that subjects carrying CYP2D6 alleles containing inactivating mutations are at higher risk for the development of Parkinson's disease. [13][14][15][16][17][18][19][20][21] Although it may be expected that this affects both subjects who are homozygous and subjects who are heterozygous for mutated alleles, most of these studies13*14 '17,18,22 did not find increased frequency of subjects with two defective alleles (poor metabolizers) but did find increased frequency of sub- jects with a single defective allele (intermediate metabolizers). Interestingly, some phenotyping studies indicated a negative correlation between the age of onset of Parkinson's disease and the oxidative capacity, 13,14*17 suggesting that subjects with one CYP2D6 mutant allele are at higher risk for the development of early-onset Parkinson's disease.…”

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confidence: 99%

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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Oxidative polymorphism of debrisoquine in Parkinson's disease.

Cited by 35 publications

References 29 publications

Debrisoquine oxidation in Parkinson's disease

Debrisoquine oxidation in Parkinson's disease

P450 enzymes and Parkinson's disease: The story so far

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

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