ENHANCED COLLAGEN-SYNTHESIS AND TRANSCRIPTION BY PEAK-E, A CONTAMINANT OF L-TRYPTOPHAN PREPARATIONS ASSOCIATED WITH THE EOSINOPHILIA-MYALGIA-SYNDROME EPIDEMIC

The pathogenesis of the eosinophilia myalgia syndrome (EMS) remains un clear, Several abnormal constituents have been found in the L-tryptoph an lots responsible for the illness, particularly, 1,1-ethylidenebis[L -tryptophan], also called peak E or EBT, and 3-phenylamino-alanine or peak 5, However, the role of these contaminants in the pathogenesis of EMS and in the development of fibrosis is unknown, We now report that peak E, a dimer of L-tryptophan, is a potent stimulus for human derma l fibroblast DNA and collagen synthesis, Peak E (0.1-1.0 mu M) increas ed DNA synthesis up to four-fold (P = 0.0001) in a dose-dependent mann er (r = 0.987), When added to monolayer cultures for 2 to 24 h, peak E (0.5 to 100 mu M) caused a progressive, more than threefold increase in alpha 1(I) procollagen mRNA levels and collagenous protein, No incr ease in procollagen mRNA levels was found after the addition of anothe r major L-tryptophan contaminant, peak 5, or with L-tryptophan itself. Transient transfection with a 2,5-kb alpha 1(I) procollagen promoter- luciferase construct shelved that peak E causes a twofold upregulation of promoter activity (P = 0.022), Contraction of collagen gels, consi sting of human dermal fibroblasts incorporated into a type I collagen lattice, was enhanced two-fold by exposure to peak E (P = 0.001), We c onclude that a major constituent of contaminated batches of L-tryptoph an, peak E, is a potent stimulus for fibroblast activation and collage n synthesis, This stimulatory action of peak E may provide a direct me chanism for the development of fibrosis in EMS.