Jump to ContentJump to Main Navigation
Show Summary Details
More options …

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

See all formats and pricing
More options …
Volume 34, Issue 2


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:
  • De Gruyter OnlineGoogle Scholar
/ Glyn B. Steventon
  • Corresponding author
  • ADMET Solutions Ltd., Ivar Gardens, Lychpit, Basingstoke, Hampshire RG24 8YD, UK, Phone: +44 (0)7786907053
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2019-04-02 | DOI: https://doi.org/10.1515/dmpt-2018-0038



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.


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


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).


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


  • [1]

    McFadden SA. Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. Toxicol 1996;111:43–65.CrossrefGoogle Scholar

  • [2]

    Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015;386:896–912.PubMedCrossrefGoogle Scholar

  • [3]

    Williams AC, Steventon GB, Sturman S, Waring RH. Heredity variation of liver enzymes involved with detoxification and neurodegenerative disease. J Metab Dis 1991;14:431–35.CrossrefGoogle Scholar

  • [4]

    Tipton KF. Might environmental factors contribute to neurodegenerative disease? Biochem Soc Trans 1995;23:429–35.CrossrefPubMedGoogle Scholar

  • [5]

    Steventon GB, Waring RH, Williams AC. Pesticide toxicity and motor neurone disease. J Neurol Neurosurg Psychiat 1990;53:621–22.CrossrefGoogle Scholar

  • [6]

    Steventon GB, Williams AC, Waring RH, Pall HS, Adams D. Xenobiotic metabolism in motorneuron disease. Lancet 1988;II:644–47.Google Scholar

  • [7]

    Steventon GB, Heafield MT, Waring RH, Williams AC. Xenobiotic metabolism in Parkinson’s disease. Neurol 1989;39:883–87.CrossrefGoogle Scholar

  • [8]

    Mitchell SC, Waring RH, Haley CS, Idle JR, Smith RL. Genetic aspects of the polymodally distributed sulphoxidation of S-carboxymethyl-L-cysteine in man. Br J Clin Pharmacol 1984;18:507–12.PubMedCrossrefGoogle Scholar

  • [9]

    Steventon GB, Sturman S, Waring RH, Williams AC. A review of xenobiotic metabolism enzymes in Parkinson’s and motor neurone disease. Drug Metab Drug Interact 2001;18:79–98.Google Scholar

  • [10]

    Waring RH, Mitchell SC. The metabolism and elimination of S-carboxymethyl-L-cysteine in man. Drug Metab Disp 1982;10:61–2.Google Scholar

  • [11]

    Boonyapiwat B, Forbes B, Steventon GB. Phenylalanine hydroxylase: possible involvement in the S-oxidation of S-carboxymethyl-L-cysteine. Anal Biochem 2004;335:91–7.PubMedCrossrefGoogle Scholar

  • [12]

    Goreish AH, Bednar S, Jones H. Mitchell SC, Steventon GB. Phenylalanine 4-monooxygenase and the S-oxidation of S-carboxymethyl-L-cysteine. Drug Metab Drug Inter 2004;20:159–74.Google Scholar

  • [13]

    Steventon GB, Mitchell SC. Mouse recombinant phenylalanine monooxygenase and the S-oxygenation of thioether substrates. Biochem Mol Toxicol 2009;23:119–24.Web of ScienceCrossrefGoogle Scholar

  • [14]

    Vandenbossche E, Lucas C, Mistry L, Garfield E, Mitchell SC, Steventon GB. Phenylalanine monooxygenase and the sulfur oxygenation of S-carboxymethyl-L-cysteine in mice. Xenobiotica 2016;46:379–84.Web of SciencePubMedCrossrefGoogle Scholar

  • [15]

    Steventon GB, Mitchell SC, Pérez B, Desviat LR, Ugarte M. The activity of wild type and mutant phenylalanine hydroxylase with respect to the C-oxidation of phenylalanine and the S-oxidation of S-carboxymethyl-L-cysteine. Mol Genet Metab 2009;96:27–31.CrossrefWeb of SciencePubMedGoogle Scholar

  • [16]

    Steventon GB, Mitchell SC. The S-oxidation of S-carboxymethyl-L-cysteine in hepatic cytosolic fractions from BTBR and phenylketonuria enu1 and enu2 mice. Xenobiotica 2019;49:495–502. DOI: .CrossrefWeb of SciencePubMedGoogle Scholar

  • [17]

    Steventon GB, Mitchell SC, Angulo S, Barbas C. An investigation into possible xenobiotic-endobiotic inter-relationships involving the amino acid analogue drug, S-carboxymethyl-L-cysteine and plasma amino acids in humans. Amino Acids 2012;42:1967–73.CrossrefWeb of SciencePubMedGoogle Scholar

  • [18]

    Boonyapiwat B, Panaretou B, Forbes B, Mitchell SC, Steventon GB. Human phenylalanine monooxygenase and thioether metabolism. J Pharm Pharmacol 2009;61:63–7.CrossrefWeb of SciencePubMedGoogle Scholar

  • [19]

    Steventon GB, Mitchell SC. Non-classical drug metabolising enzymes. Lett Drug Des Discov 2006;3:405–12.CrossrefGoogle Scholar

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.

Export Citation

© 2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Stephen C. Mitchell and Glyn B. Steventon
Xenobiotica, 2019, Page 1

Comments (0)

Please log in or register to comment.
Log in