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Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Editorial Board: Benjeddou, Mongi / Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.


CiteScore 2018: 1.01

SCImago Journal Rank (SJR) 2018: 0.277
Source Normalized Impact per Paper (SNIP) 2018: 0.446

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2363-8915
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Volume 34, Issue 2

Issues

Drug S-oxidation and phenylalanine hydroxylase: a biomarker for neurodegenerative susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis

Lucinda Rawlings / Laura Turton / Stephen C. Mitchell
  • Section of Computational and Systems Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
  • Other articles by this author:
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/ Glyn B. Steventon
  • Corresponding author
  • ADMET Solutions Ltd., Ivar Gardens, Lychpit, Basingstoke, Hampshire RG24 8YD, UK, Phone: +44 (0)7786907053
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  • Other articles by this author:
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Published Online: 2019-04-02 | DOI: https://doi.org/10.1515/dmpt-2018-0038

Abstract

Background

The S-oxidation of S-carboxymethyl-L-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis. In the present investigation, the original observations have been extended and confirmed.

Methods

Meta-analysis of previously published investigations into the S-oxidation polymorphism together with new subject data was evaluated.

Results

The incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) was found to be 3%–7% within healthy and non-neurological disease populations, whereas 38% of the Parkinson’s disease subjects and 39% of the amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson’s disease was calculated to be 33.8 [95% confidence interval (CI), 13.3–86.1] and for amyotrophic lateral sclerosis was 35.2 (95% CI, 13.0–85.1).

Conclusions

The possible involvement of the enzyme responsible for this S-oxidation biotransformation reaction, phenylalanine hydroxylase, should be further investigated to elucidate its potential role in the mechanism(s) of toxicity in susceptible individuals displaying these diseases. The “Janus hypothesis,” possibly explaining why phenylalanine hydroxylase is a biomarker of neurodegenerative disease susceptibility, together with the general theme that this concept may apply to many other hitherto unsuspected enzyme systems, is presented.

Keywords: phenylalanine hydroxylase; polymorphism; S-oxidation biomarker

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About the article

Received: 2018-12-04

Accepted: 2019-02-11

Published Online: 2019-04-02


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Drug Metabolism and Personalized Therapy, Volume 34, Issue 2, 20180038, ISSN (Online) 2363-8915, DOI: https://doi.org/10.1515/dmpt-2018-0038.

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