A murine model of the eosinophilia-myalgia syndrome induced by 1,1'-ethylidenebis (L-tryptophan).

Abstract

The eosinophilia-myalgia syndrome (EMS) is a recently described disease that has been associated with the ingestion of L-tryptophan containing trace amounts of several impurities. The first such contaminant to be identified and linked epidemiologically to the EMS epidemic was 1,1'-ethylidenebis(L-tryptophan) (EBT), but its role in the etiology and pathogenesis of the syndrome has been controversial. We report the development of inflammation and fibrosis affecting the dermis and subcutis, including the fascia and perimyseal tissues, after the daily intraperitoneal administration of EBT to female C57BL/ 6 mice. Such changes are accompanied by increased numbers of mast cells, many of which appear to be degranulating. Plasma levels of quinolinic acid, a metabolic product of L-tryptophan via the kynurenine pathway, are reduced initially, and then become elevated when inflammation and fibrosis are more pronounced. The nature and location of the inflammatory cell infiltrate and fibrosis, as well as the presence of mast cells and alterations of L-tryptophan metabolism, are consistent with findings reported in patients with EMS. This murine model suggests that EBT may have been one of the mediators of EMS and should facilitate studies of the pathogenesis of EMS. (J.

Safety of 5-hydroxy-l-tryptophan

“…Further studies showed that direct feeding of synthetic EBT alone resulted in similar findings (Love et al, 1993). Silver et al (1994) used C57BI/6 mouse as a model. Female mice were given daily intraperitoneal injections of saline, control l-Trp, EBT, or control l-Trp with EBT.…”

Does 5-Hydroxytryptophan Cause Acute and Chronic Toxic Perturbations in Rats?

“…Accordingly, similar to the previous studies using contaminated LT or 1,1'-ethyldenebis(tryptophan) (EBT), believed by some to be the causative factor in Peak E, to produce EMS-like signs rats (Crofford et al 1990;DeSchryver-Kecskemeti et al 1991;Love et al 1993;Ogawa et al 1993;Silver et al 1994;Mio et al 1994), we attempted to reproduce the findings in rats using low-and-high dose levels of commercial 5-HTP. Our source of 5-HTP came from the manufacturer said to have the most Peak X material in their product (Klascov et al 2003).…”

Effect of melatonin on the induction of foci of aberrant crypts in the colon by azoxymethane in rats

“…In addition, it was found that melatonin had a sleep evoking effect, just as did tryptophan (40,41). The latter compound had been used frequently for the clinical management of insomnia, but came into disuse when a product on the market was contaminated with 1,1'-ethylidene-bis-α-tryptophan, that seemed to be responsible for the eosinophylia-myalgia syndrome and related diseases (34,42,43). It now seems clear that the reason tryptophan was found beneficial in inducing sleep because it was converted biochemically to melatonin (41).…”