Metabolism and distribution in the rat of peak E substance, a constituent in L-tryptophan product implicated in eosinophilia-myalgia syndrome.
Peak E substance, 1,1'-ethylidenebis[tryptophan], a contaminant found in L-tryptophan tablets, has been suggested as a causative agent for eosinophilia-myalgia syndrome (EMS). Peak E substance (50 mg/kg) was administered perorally to Wistar rats to determine its metabolism and distribution. A purification procedure using Bond Elut C8 cartridges followed by HPLC was developed for the determination of peak E substance. The plasma concentration of peak E substance was 136 ng/ml at 1 h, and urinary excretion was 717 ng at 5 h and 10342 ng for 5-24 h, showing slow excretion of peak E substance into urine. The amount of peak E substance in the contents of the large intestine at 5 h, however, was 3136 micrograms, much greater than urinary excretion for 24 h, indicating considerable transfer of peak E substance to large intestine without decomposition by gastric fluid in the stomach. We have detected for the first time not only the occurrence of peak E substance in plasma and urine, but also 1-methyl-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) in blood and organs of rats treated with peak E substance, thereby suggesting MTCA as one of the the metabolites of peak E substance. The amount of MTCA in the contents of the large intestine as well as in urine of rats treated with peak E substance was significantly greater than in L-tryptophan-treated rats (50 mg/kg p.o.), demonstrating that MTCA was more readily produced from peak E substance than from L-tryptophan. Finally, we propose acetaldehyde-induced production of MTCA from peak E substance.
Department of Legal Medicine, Kobe University School of Medicine, Japan.
J
J
Adachi
T
T
Naito
Y
Y
Ueno
Y
Y
Ogawa
I
I
Ninomiya
Y
Y
Tatsuno
D000818:Animals; D002243:Carbolines / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D016603:Eosinophilia-Myalgia Syndrome / Q000139:chemically induced*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism
D002243:Carbolines; C070372:1,1'-ethylidene bis(tryptophan); C038114:1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid; D014364:Tryptophan