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PubMed1996

Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome.

Evidence from an array of scientific studies strongly supports the conclusion that ingestion of products containing L-tryptophan (LT) produced by Showa Denko KK caused the 1989 epidemic of eosinophilia-myalgia syndrome (EMS) in the United State. In case-control studies of EMS, LT exposure was essentially universal among cases but rare among controls. Of 6 manufacturers of LT, only LT manufactured by Showa Denko KK was clearly associated with illness. The data meet other Hill criteria for inferring a causal relationship. Consistent findings were found in multiple independently conducted studies. There was a dose-response effect, with risk of illness increasing as a function of the amount of tryptophan consumed. The extremely small p values observed in the multiple independently conducted studies effectively rule out the possibility that the tryptophan-EMS association was the result of chance. Moreover, no potential confounding factor or bias explains the association. The incidence of EMS in the United States diminished abruptly once LT containing products were recalled.

Drug Industry↗
PubMed1992

Competitive studies relating to tryptophan binding to rat hepatic nuclear envelopes as a sensitive assay for unknown compounds.

Our laboratory has reported that L-tryptophan binds to a rat liver nuclear envelope protein and this binding is saturable, stereospecific and of high affinity. Utilizing an in vitro [3H]tryptophan binding assay to hepatic nuclear envelopes, we have determined the effects of using excess unlabeled L-tryptophan from a number of different suppliers. This study reports that, based on our in vitro binding assay, some significant differences were observed when implicated L-tryptophan in cases of the eosinophilia-myalgia syndrome obtained from a Japanese manufacturer, Showa Denko, was assayed, in contrast to non-implicated L-tryptophan from other suppliers. An isolated impurity of Showa Denko L-tryptophan, 1,1'-ethylidenebis(tryptophan) alone or together with non-implicated L-tryptophan or its breakdown product, 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, did not appreciably affect the in vitro [3H]tryptophan binding to hepatic nuclear envelopes as did the Showa Denko L-tryptophan. Our data, derived with our in vitro binding assay system, suggests that implicated L-tryptophan from Showa Denko contains a compound/s (unknown at present) other than 1,1'-ethylidenebis(tryptophan), which alters in vitro [3H]tryptophan binding. The significance of the impurity/ies involved remains to be determined.

Animals↗
PubMed1993

Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York.

Using a case-control study design, patients with eosinophilia myalgia syndrome (EMS) who had used L-tryptophan (LT) were compared with LT users who did not develop EMS. Of the 113 case patients and 95 controls who had used a retail brand that could be traced to a bulk LT producer, all (100%) case-patients and 69 (73%) controls used LT brands that were traced to Showa Denko K.K. (lower 95% CL = 10.0). Among the users of LT produced by Showa Denko K.K., the risk of EMS was greater for persons who used LT produced after December 1, 1988 (OR = 25.8, [95% CL = 7.1, 101.4]). The risk of developing EMS increased with increased dosage of LT, increased age, and use of LT as a sleeping aid. These epidemiologic data support the hypothesis that the etiologic agent in EMS is a contaminant introduced into LT products during production.

Adolescent↗
PubMed1997

Mouse strain and source of L-tryptophan affects hepatic nuclear tryptophan binding.

This study describes that the affinity for specific L-tryptophan binding to hepatic nuclei in vitro is markedly decreased in NZBWF1 mice in comparison to that in Swiss mice. Also, the hepatic nuclei of NZBWF1 mice have a significantly decreased binding response in vitro to Showa Denko L-tryptophan (implicated in the eosinophilia-myalgia syndrome) or to its contaminants, 1,1'-ethylidenebis(tryptophan) or 3-phenylamino-L-alanine, when each is added to control, non-implicated L-tryptophan compared with hepatic nuclei of Swiss mice. Enhanced hepatic protein synthesis induced by tube-feeding control L-tryptophan is much less in NZBWF1 mice than in Swiss mice. Tube-feeding of Showa Denko L-tryptophan induced less stimulation of hepatic protein synthesis than did control L-tryptophan in Swiss mice but essentially none in NZBWF1 mice. NZBWF1 mice have a genetically altered response to L-tryptophan which may prove to be useful is studying the role of L-tryptophan in health and in disease.

Alanine↗
PubMed1993

Eosinophilia-myalgia syndrome in patients ingesting a single source of L-tryptophan.

OBJECTIVE: To estimate the attack rate for eosinophilia-myalgia syndrome and to identify potential risk factors for illness among patients attending a New York City medical clinic, who purchased L-tryptophan containing products produced exclusively by Showa Denko K.K. METHODS: A case-control design was used. Cases and controls purchased L-tryptophan containing products at the medical clinic from July 1, 1989--December 1, 1989. All case-patients identified with illness onset during the study period were included. Controls were selected by a systematic sample of the 683 purchasers of L-tryptophan attending the same clinic. RESULTS: Twelve (2.2%) of an estimated 553 L-tryptophan users were case-patients. Multivariate analysis suggested that lot 2 use (adjusted odds ratio [OR] = 35.9), concomitant use of chromium (adjusted OR = 12.3), and concomitant use of pyridoxine (adjusted OR = 5.8) were associated with the development of illness. Chemical analysis of tablets corresponding to the 3 Showa Denko K.K. lots ingested by study participants showed that lot 2 had the highest concentration of ethylidenebis (L-tryptophan), a proposed causative agent or marker for a causative agent in the eosinophilia-myalgia syndrome. CONCLUSIONS: Information from our study of persons exposed to implicated L-tryptophan supports the role for a contaminant as the causative agent in the eosinophilia-myalgia syndrome and identifies possible cofactors that deserve further study.

Case-Control Studies↗
PubMed1993

Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome.

In late 1989, an epidemic of eosinophilia-myalgia syndrome (EMS) that resulted in several thousand cases of the syndrome and 36 deaths was recognized in the United States. Physicians in New Mexico linked the epidemic to the ingestion of L-tryptophan (LT). Results of studies indicated that one or more trace contaminants in LT were likely causes of the EMS epidemic. Investigators traced the LT that was taken by most patients with EMS to a single manufacturer, Showa Denko K.K. of Japan. We now report results of high performance liquid chromatographic analysis of LT samples from this manufacturer. Three sets of blind-coded samples were analyzed: the priority case lot set, which included 54 case-associated LT lots and 50 noncase-associated LT lots that were taken by case and control subjects who used only one brand of LT; the single lot case set, which included 73 case-associated LT lots and 25 noncase associated LT lots taken by case and control subjects who used only a single lot of LT; and the South Carolina tablet set, which included LT tablets taken by case subjects (n = 26) and by control subjects (n = 52). We statistically compared the concentration of each contaminant in case-associated, noncase-associated, and control samples of each sample set. The analyses showed that there were more than 60 minor contaminants in the LT from Showa Denko K.K., and that six of these contaminants were associated with EMS. The structures of three contaminants are known, but the identities of the other three contaminants are currently unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacillus↗
PubMed1994

Studies with 1,1'-ethylidenebis(tryptophan), a contaminant associated with L-tryptophan implicated in the eosinophilia-myalgia syndrome.

L-Tryptophan binds to a rat liver nuclear envelope protein, and this binding is saturable, stereospecific, and of high affinity. Utilizing an in vitro assay of [3H]tryptophan binding to rat hepatic nuclear envelopes, we have previously determined that the L-tryptophan obtained from Showa Denko and which was implicated in cases of the eosinophilia-myalgia syndrome (EMS) inhibited [3H]tryptophan binding differently than did control L-tryptophan (not implicated in EMS). Therefore, in this study we investigated whether the addition of 1,1'-ethylidenebis(tryptophan) (EBT), a contaminant or impurity in L-tryptophan implicated in EMS, would have an effect. Our results indicate that EBT alone has little inhibitory binding effect compared with that of control L-tryptophan and that when EBT was added to control L-tryptophan the inhibitory binding effort was similar to that of control L-tryptophan alone. On the other hand, in vitro addition of EBT plus L-tryptophan to nuclei of cultured murine macrophages (WLG5) results in less inhibition of [3H]-tryptophan binding than does addition of L-tryptophan alone. Similar in vitro additions to nuclei of rat brain reveal little effect on binding, as was also the case for hepatic nuclear envelopes. Adding EBT to an in vitro hepatic protein synthesis system and measuring [3H]tryptophan incorporation into acid-precipitable proteins reveal that it competes similarly to that found with equimolar concentrations of unlabeled L-tryptophan. It does not affect [14C]leucine incorporation into proteins. [14C]EBT becomes incorporated in vitro into proteins (acid-precipitable), and this incorporation is diminished in the presence of equimolar concentrations of unlabeled EBT or L-tryptophan. This suggests that EBT or possibly a breakdown product becomes incorporated into proteins. Speculation as to how EBT may affect tissues in experimental animals is presented.

Animals↗
PubMed1999

Structural characterization of case-associated contaminants peak C and FF in L-tryptophan implicated in eosinophilia-myalgia syndrome.

We have characterized the structures of two case-associated contaminants of the Showa Denko L-tryptophan known to cause eosinophilia-myalgia syndrome (EMS). A combination of on-line accurate mass HPLC-electrospray ionization-mass spectrometry (LC-MS), HPLC-tandem mass spectrometry (LC-MS-MS) and HPLC-in source collision induced dissociation-MS-MS (LC-sCID-MS-MS) allowed the structure determination of both Peak C and FF. Peak C is identified as 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2-3b]-indole-2-carboxyl ic acid, whereas Peak FF is characterized as 2-(2-hydroxy-indoline)-tryptophan. Both contaminants contain indoline rings, and the significance of this finding is discussed.

Chromatography, High Pressure Liquid↗
PubMed1999

Synthesis, formation, and occurrence of contaminants in biotechnologically manufactured L-tryptophan.

The pattern of contaminants in pharmaceutical and feed grade L-tryptophan (Trp) was investigated in a market survey of 22 lots of 6 different manufacturers. To date, 5 case associated contaminants in Showa Denko tryptophan (SD-Trp) known to cause the autoimmune disease eosinophilia-myalgia syndrome (EMS) have been structurally elucidated: 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrroloindole-2-carboxylic acid (PIC), an indoline compound, is one of the most abundant degradation compounds of unbound Trp during oxidative treatment. 2-(3-indolylmethyl)-L-tryptophan (IMT) and 2-(2-hydroxyindoline)-tryptophan (HIT) are both 2-substituted Trp-derivatives. IMT was synthesized by the reaction of Trp and indole-3-methanol or indole-3-acetaldehyde, respectively. From this finding it is proposed that Trp-metabolites can decompose under formation of transitional, mesomerism-stabilized cations that react with excess Trp to yield 2-substituted Trp derivatives. The decomposition of Trp-metabolites could be induced by elevated or low pH-values that occur during the downstream processing of the Trp fermentation broth. IMT was detected in pharmaceutical-grade and feed-grade Trp in amounts of < 20-1,400 mg/kg. 1,1'-Ethylidenebis-(L-tryptophan) (EBT) is formed from acetaldehyde and Trp under acidic conditions and serves as a marker for EMS-suspicious Trp. 3-(Phenylamino)alanine (PAA) is the only not Trp derived case associated contaminant. Low amounts of PAA (20 mg/kg) could be detected in feed-grade Trp of one manufacturer. Non-EMS correlated 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acids of Trp and formaldehyde, acetaldehyde and indole-3-acetaldehyde could be detected in the examined Trp raw materials (< 10-13,500 mg/kg). In order to guarantee the safety of Trp containing drugs the amount of EBT (< 10 mg/kg Trp) and the sum of UV220 nm detectable contaminants (< 400 mg/kg Trp) are limited by the European authorities.

Animal Feed↗
PubMed1998

On-line HPLC-tandem mass spectrometry structural characterization of case-associated contaminants of L-tryptophan implicated with the onset of eosinophilia myalgia syndrome.

The eosinophilia-myalgia syndrome (EMS) outbreak that occurred in the USA in 1989 was caused by the intake of L-tryptophan (Trp) produced from one manufacturer, Showa Denko K.K. of Japan. Six compounds present in the Trp were reported to be case-associated contaminants. However, three of these compounds, Peaks C, FF and AAA have remained unidentified. Here, we successfully employ on-line HPLC-electrospray ionization multistage mass spectrometry to structurally characterize Peak C and Peak FF. Peak C was determined by accurate mass-LC-MS to have a protonated molecular ion MH+ = 221.0919 with an empirical formula of C11H13N2O3. By comparing the LC-MS-MS spectra with authentic 5-OHTrp and other structurally similar compounds, as well as considering the chemical reactivity of the indole ring, the structure of Peak C was consistent with 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]-indole-2-carboxy lic acid. Peak FF was also subjected to accurate mass-LC-MS and shown to have MH+ = 338.1524, corresponding to an empirical formula of C19H20N3O3. Comparison of the LC-MS-MS and LC-sCID-MS-MS of spectra derived from Peak FF with a previously characterized contaminant of Trp, namely P31, was consistent with Peak FF being 2-(2-hydroxy indoline)-Trp. Unlike the majority of the contaminants identified in EMS implicated tryptophan, both Peaks C and FF possess an indoline ring. This is significant since a case-associated contaminant found in 5-hydroxy-Trp also contains an indoline ring, and the chemical reactivity of this ring system may possibly play a role in the etiology of EMS.

Chromatography, High Pressure Liquid↗
PubMed1991

[Eosinophilia-myalgia syndrome].

The following is an outline of one typical case of chronic eosinophilia-myalgia syndrome (EMS). In 1987 a 62-year-old woman began taking L-tryptophan, 1.5 g nightly, due to sleeping difficulty. During the months preceding the appearance of EMS she continued to take L-tryptophan, derived from the biosynthetic production of the Japanese manufacturer "Showa Denko". She has suffered increasingly from severe myalgia and a proximal muscle weakness since July of 1989. In November, 1989 her white blood cell count measured 12.1 X 10(9)/l with 3.6 X 10(9) eosinophil cells/l. The bone marrow exhibited an increased granulopoesis and an extreme increase in the amount of eosinophil cells. The muscle biopsy specimen indicated an inflammation with perivascular distribution. The eosinophil cell count of the blood was quickly normalized via the introduction of prednisone over a short period. In the absence of further immunosuppressive therapy a slow improvement can be seen in the myalgia and in her general condition. Since the beginning of 1990 there has been a slow development of hyperpigmented scleroderma-like skin changes with distal distribution.

Biopsy↗
PubMed1985

[Evaluation of the malignancy of breast carcinoma using flow cytometry].

Flow cytometric DNA analyses of single cell nuclei were performed on nuclear suspensions prepared from tumors of primary breast carcinomas in 40 patients operated on in our hospital. Fluorescence intensities of propidium-iodide stained cell nuclei were analyzed in a SHOWA DENKO SC-20 cell sorter. The DNA index and the percentage of S-phase cells and DNA aneuploidy were calculated from each DNA histogram. There was a tendency for more advanced nodal tumor involvement to have a higher DNA index, increasing DNA aneuploidy proportions and significantly larger percent of S-phase cells.

Adenocarcinoma, Mucinous↗