Tryptophan toxicity--time and dose response in rats.
During the past decade L-tryptophan (Trp) ingestion have been associated with a multisystemic syndrome, known as eosinophilia myalgia syndrome (EMS). Even though an epidemic studies indicated that a contaminant, 1,1'-ethylidene-bis-L-tryptophan was involved in EMS, abnormalities in metabolism of Trp have been reported in other similar clinical syndromes such as carcinoid syndrome, scleroderma or eosinophilic fasciitis. The purpose of the study was to investigate the role of Trp or its metabolite, given in different dosing regimens in induction of tissue damage.


METHODS
3 months old female rats (Charles River CD-1) were fed for 3, 6, 12 weeks on a diet containing 20% protein diet derived from casein and supplemented with 1%, 2%, or 5% Trp. On the last week of feeding, half of the animals fed on a control diet and half of the animals fed on the Trp diet were injected with 2 injections of para-chlorophenyl alanine (p-CPA), a Trp hydroxylase inhibitor, 300 mg/kg i.p. followed by 3 injection of 100 mg/kg every alternate day.


RESULTS
Body weight of rats fed higher levels of Trp increased slowly and injection of p-CPA induced loss in body weight. 2/6 of the animals treated with 1% Trp and 1/6 treated with 5% Trp for 3 weeks and 2/4 animals treated with 1% Trp and 1/4 treated with 5% Trp for 12 weeks died after injection of p-CPA. No mortality was detected in 1-5% Trp treated animals. Alopecia and skin changes were seen after p-CPA in 1-5% Trp treated animals. Increased amounts of connective tissue and induction of inflammatory cell proliferation were observed in lung, spleen and in gastrocnemia muscle of rats treated with higher dose of Trp for longer period. Induction of kynurenine pathway by injection of p-CPA caused more tissue damage. It is concluded that excessive Trp or elevation of its metabolites could play a role in amplifying some of pathological features of EMS. This pathological damage is further augmented by metabolites of the kynurenine pathway.
Gross
B
B
Department of Neurology, Carmel Medical Center, Faculty of Medicine, Haifa, Israel. bgross@netvision.net.il
Ronen
N
N
Honigman
S
S
Livne
E
E
D000505:Alopecia / Q000139:chemically induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D005260:Female; D010134:Fenclonine / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014364:Tryptophan / Q000008:administration & dosage / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015431:Weight Loss / Q000187:drug effects
D014409:Tumor Necrosis Factor-alpha; D014364:Tryptophan; D010134:Fenclonine