Letters to the Editor pubs.acs.org/crt
Letter to the Editor Regarding the Article by Natsch et al., 2015
N
atsch et al.1 have suggested that hydroperoxides can sensitize by a nonspecific pathway, producing an electrophilic species, N-formyl-kynurenine, from oxidative breakdown of a tryptophan-peptide. N-Formyl-kynurenine had previously been implicated2 as the common proteinreactive species responsible for cross-reactivity among structurally unrelated photoallergens. In support of their proposal, Natsch et al. report the formation of N-acetyl-N′-formylkynurenine-OMe from the incubation of N-acetyl-O-methyltryptophan with several hydroperoxides. Natsch et al.1 propose that this pathway could explain cases of dermatitis patients being found to be sensitized to hydroperoxides derived from terpenes used in fragrances, even though the fragrances do not contain any one hydroperoxide at a concentration approaching its own potency level. In response, Karlberg et al.3 argue that Natsch et al.1 have ignored evidence that hydroperoxides have been found to be noncross-reactive with each other, and they point out that the N-formyl-kynurenine derivative is formed to a lesser extent in the hydroperoxide incubation studies than it is in the photosensitizer studies and that in the absence of an appropriate control experiment there is no firm evidence to show that the N-formyl-kynurenine derivative is formed by reaction of hydroperoxides to an extent greater than that formed without hydroperoxides present. With regard to the argument of noncross-reactivity, this is not completely inconsistent with the Natsch et al.1 hypothesis. Suppose each hydroperoxide can react with protein to produce a specific modification (SM) and at the same time react with tryptophan units to form the electrophilic N-formyl-kynurenine derivative, which gives the same nonspecific modification (NSM) whatever the hydroperoxide. Suppose that when a single hydroperoxide is tested on its own, the threshold level of SM is reached before the threshold of NSM. Then, the person or animal will be sensitized specifically and will not be sensitized to other hydroperoxides. Now, suppose we have a mixture of hydroperoxides, each one at a level below its own threshold level for SM. These SM levels are not additive, so the people or animals do not become sensitized by the SM mechanism. The hydroperoxides are all below their individual NSM threshold levels too, but these are additive, so the total NSM level can reach the threshold, resulting in people or animals being sensitized by the nonspecific mechanism. Because elicitation thresholds are usually lower than sensitization thresholds, when NSM-sensitized subjects are challenged with a single hydroperoxide, the degree of NSM produced at challenge may be enough to produce a positive response. So, the Natsch et al.1 suggestion of a nonspecific pathway involving the N-formyl-kynurenine derivative remains plausible, but unless stronger evidence can be produced, it remains no more than a plausible hypothesis. In particular, a serious weakness is the absence of the control experiments suggested by Karlberg et al.3 to determine whether the tryptophanderived N-formyl-kynurenine derivative is formed to the same extent with or without hydroperoxide present. © 2015 American Chemical Society
David W. Roberts*
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School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, England
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
REFERENCES
(1) Natsch, A., Emter, R., Badertscher, R. P., Brunner, G., Granier, T., Kern, S., and Ellis, G. (2015) Oxidative Tryptophan Modification by Terpene- and Squalene-Hydroperoxides and a Possible Link to CrossReactions in Diagnostic Tests. Chem. Res. Toxicol. 28, 1205−1208. (2) Karlsson, I., Persson, E., Ekebergh, A., Martensson, J., and Borje, A. (2014) Ketoprofen-Induced Formation of Amino Acid Photoadducts: Possible Explanation for Photocontact Allergy to Ketoprofen. Chem. Res. Toxicol. 27, 1294−1303. (3) Karlberg, A. T., Borje, A., Lepoittevin, J.-P., Giménez-Arnau, E., Brared Christensson, J., and Hagvall, L. (2015) Letter to the Editor regarding the article by Natsch et al., 2015. Chem. Res. Toxicol., DOI: 10.1021/acs.chemrestox.5b00306.
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EDITOR'S NOTE Dr. David Roberts was invited by Chemical Research in Toxicology to contribute a Letter to the Editor.
Published: October 23, 2015 2085
DOI: 10.1021/acs.chemrestox.5b00426 Chem. Res. Toxicol. 2015, 28, 2085−2085
