Safety studies of l-alanyl-l-glutamine (l-AG).
The safety of l-alanyl-l-glutamine (l-AG) derived by fermentation using a recombinant Escherichia coli strain containing the l-amino acid alpha-ligase gene from Bacillus subtilis, was assessed in acute and subchronic toxicity studies in the rat. l-AG was tested in vitro in a bacterial reverse mutation assay and in a chromosome aberration assay. l-AG was not acutely toxic when administered to Sprague-Dawley rats by gavage at 2000mg/kg bw. In a 14-day range-finding study, l-AG at up to 5% in the diet was without effect. In the 13-week dietary study, there were no toxicologically significant differences between the treated groups (1.0, 3.0 and 5.0% l-AG) and the controls (0% and 5% l-AG produced via a different method) with respect to body weight gain, feed consumption, feed efficiency, or the results of ophthalmological, haematological, clinical chemistry, and urinalysis evaluations. Three of 10 high-dose males had mild testicular changes, however, these were of exactly the same nature and severity as those that occur spontaneously, and were considered unlikely to be treatment-related. The NOAEL in both males and females was established as the highest dose tested at 3129 and 3601mg/kg bw/day, respectively (5.0% in the diet). There was no evidence of genotoxicity of l-AG in the Ames assay or in the in vitro CHL cell chromosome aberration study.
Oda
S
S
Gotemba Laboratory, Bozo Research Center, Inc., 1284, Kamado, Gotemba-city, Shizuoka 412-0039, Japan.
Mullaney
T
T
Bowles
A J
AJ
Durward
R
R
Lynch
B
B
Sugimura
Y
Y
D000818:Animals; D001774:Blood Chemical Analysis; D002460:Cell Line; D002869:Chromosome Aberrations / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005502:Food / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008297:Male; D009152:Mutagenicity Tests; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012727:Sex Characteristics; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D004151:Dipeptides; C054122:alanylglutamine