Update: Analysis of L-Tryptophan
for the Etiology of Eosinophilia-Myalgia Syndrome
In August 1990, CDC and the Food and Drug Administration
proposed a structure for peak 97 (Figure 1A), the high
performance liquid chromatographic (HPLC) peak that was most
predictive of L-tryptophan (LT) lots associated with
eosinophilia-myalgia syndrome (EMS) cases( 1). This report
updates those findings.
Analyses of the product of LT and acetaldehyde show that the
product is the di-L-tryptophan aminal of acetaldehyde (DTAA),
with the methine bridge coupling the two tryptophan molecules
across the indolenitrogens (Figure 1B) rather than the amino
nitrogens (Figure 1A). This synthesized product has the same
proton nuclear magnetic resonance (NMR) spectra, mass spectra,
and HPLC chromatographic properties as peak 97. Key information
to support the location of the methine bridgewas provided by the
analyses of synthesized product using a two-dimensional
long-range 13C-1H shift correlation NMR spectroscopic experiment
(2), which demonstrated that the methine proton of the
acetaldehyde residue is coupled to carbons 2 and 2' of the LT
groups and that protons 2 and 2' of these groups are
correspondingly spin-coupled to the methine carbon of the
acetaldehyde residue. This experiment could not be performed on
the limited quantity of peak 97 collected from the
case-associated lots. In addition, chemical derivatization
experiments with the synthesized material and with model
compounds are consistent with Figure 1B but not with 1A.
Reported by: Center for Food Safety and Applied Nutrition, Food
and Drug Administration. Center for Environmental Health and
Injury Control, CDC.
Editorial Note
Editorial Note: This confirmation of the structure of peak 97 as
the DTAA shown in Figure 1B will enable testing of the correct
compound for its biologic effects and assessment of any
structure-activity relationship. Studies of the biologic effects
of synthesized DTAA--including evaluation of the recently
developed rat model for EMS(3)--are in progress. Clarification
regarding the role of peak 97 may be important in understanding
the pathophysiology of EMS and similar diseases (e.g.,toxic-oil
syndrome).
References
CDC. Analysis of L-tryptophan for the etiology of
eosinophilia-myalgia syndrome. MMWR 1990;39:589-91.
Reynolds WF, McClean S, Perpick-Dumont M, Enriquez RG.Improved
13C-1H shift correlation spectra for indirectly bonded carbons
and hydrogens: the FLOCK sequence. Magn ResonChem 1989;27:162-9.
Crofford LJ, Rader JI, Dalakas MC, et al. L-Tryptophan
implicated in human eosinophilia-myalgia syndrome causes
fasciitis and perimyositis in the Lewis rat. JClin Invest
1990;86:1757-63.
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