Neurotoxic effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on dogs.
In order to clarify the mechanism of the neurotoxicity of 5-FU and/or its masked compounds, we studied the effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on the formation of vacuolar changes in the dog cerebrum, using the dosage of 3.0 mg/kg/day of FBAL-HCl (FBAL x HCl) and 0.03 mg/kg/day of FA-Na (FA x Na), respectively. These 2 compounds were selected because they are the metabolites of 5-FU claimed to be responsible for the neurotoxic effects of 5-FU and/or its masked compounds, and we wanted to confirm their effects. Tegafur-uracil mixture (UFT) was used as a positive control drug for the formation of vacuolar changes in the dog cerebrum. All compounds were orally administered daily for 3 months to beagle dogs. Each study group consisted of 3 males. Neurotoxic signs such as hyperesthesia and/or excitement, as well as convulsions, were observed in both FBAL x HCl and FA x Na groups; these toxic signs were also found in the UFT group. Slight loss of body weight gain and of food consumption was observed in the FBAL x HCl and UFT groups. Neuropathologically, vacuolar changes were detected in several areas of the dog cerebrum following administration of FBAL x HCl, FA x Na or UFT. In terms of morphology, the neuropathological effects of these 2 drugs were very similar to those induced by UFT. In conclusion, we clearly showed that FBAL is one of the main substances that cause neurotoxic signs and neuropathological changes in dogs intoxicated by 5-FU or its masked compounds. Moreover, FA might be considered to be a causative factor in addition to FBAL.
Yamashita
Kazumasa
K
Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan.
Yada
Hideaki
H
Ariyoshi
Toshihiko
T
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D005463:Fluoroacetates / Q000008:administration & dosage / Q000633:toxicity*; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity; D006941:Hyperesthesia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D012378:Rodenticides / Q000008:administration & dosage / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013687:Telencephalon / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D018675:Toxicity Tests / Q000379:methods*; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*
D005463:Fluoroacetates; D012378:Rodenticides; D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine; C014815:fluoroacetic acid; D005472:Fluorouracil