Use of ADME studies to confirm the safety of epsilon-polylysine as a preservative in food.
Epsilon-polylysine is a homopolymer of L-lysine, containing approximately 30 L-lysine subunits, as synthesized in aerobic bacterial fermentation by Streptomyces albulus. epsilon -Polylysine is approved for food use in Japan as an antimicrobial preservative. A series of pharmacokinetic and metabolic profile studies on epsilon -polylysine have been conducted in rats in order to provide a better understanding of the reason for its lack of toxicological effects in subchronic and chronic feeding bioassays using relatively high concentrations in the diet up to 50000 ppm. As reported in this article, epsilon -polylysine was practically non-toxic in an acute oral toxicity study in rats, with no mortality up to 5 g/kg and was not mutagenic in bacterial reversion assays. Absorption, distribution, metabolism and excretion (ADME) studies on 14C-radiolabeled epsilon -polylysine, given in a single dose to fasted male rats at 100mg/kg, revealed low absorption from the gastrointestinal tract. All but trace amounts of the dosed radioactivity was eliminated by excretion within 168 h and over 97% was accounted for in urine (1.2%), feces (92.9%), or expired air (3%) by 48 h. The sum of the cumulative excretion with routes associated with absorption in urine, expired air and carcass was 6.4% of total recovered radioactivity; approximately 94% of the dose of epsilon -polylysine passed unabsorbed through the gastrointestinal tract in the feces. Whole body autoradiography did not show concentration of absorbed epsilon -polylysine in any tissue or organ. Excretion half-lives of epsilon -polylysine equivalents in blood and plasma were 20 and 3.9 days, likely prolonged by the incorporation into protein of cleaved L-lysine. Metabolic profiles by HPLC analysis of plasma samples suggest that L-lysine is the predominant early metabolic by-product, likely from protease activity in the upper GI tract; only 0.2% of the administered parent compound was found in plasma. At 8-72 h, HPLC profiles show diminishing levels of epsilon -polylysine and L-lysine in plasma, accompanied by a shift to larger peaks of homopolymer fragments of varying subunit length, presumably from microbial degradation of epsilon -polylysine in the lower gut. HPLC profiles of urine and feces collected from 0 to 24 h post-dosing revealed three distinct peaks in urine, the first peak likely to be epsilon -polylysine and epsilon -polylysine less a few amino acid subunits, and the second, L-lysine and the third, a metabolite of L-lysine. Radiolabeled L-lysine was reduced from 67.2% of the radioactivity in plasma at 30 min to 7.5% at 4 h, indicating that L-lysine is readily removed from plasma from essential amino acid incorporation into protein. Based on the findings of the ADME studies and lack of toxicity in safety studies, the proposed use of epsilon -polylysine as a preservative in foods is considered to be safe.
Hiraki
Jun
J
Chisso Corporation, Yokohama, Japan.
Ichikawa
Takafumi
T
Ninomiya
Shin-ichi
S
Seki
Hideaki
H
Uohama
Katsumi
K
Seki
Hiroshi
H
Kimura
Shigemi
S
Yanagimoto
Yukio
Y
Barnett
James W
JW
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D005260:Female; D005520:Food Preservatives / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D011107:Polylysine / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests / Q000379:methods*
D005520:Food Preservatives; D009153:Mutagens; D011107:Polylysine