title: Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): IV. Assessment of the repeated-dose toxicological potential of synthesized L-valyl-L-prolyl-L-proline in male and female rats and dogs.
abstract: The objective of these repeated-dose, 8-week studies was to assess the toxicological potential of a synthetic tripeptide, L-valyl-L-prolyl-L-proline (VPP), when administered to Charles River rats and Beagle dogs. Groups of 20 male and 20 female rats were fed powdered diets containing sufficient VPP to afford daily doses of 0, 2, 8, or 16 mg/kg body weight (BW)/day. Groups of five male and five female dogs were administered 0, 2, 8, or 16 mg/kg BW/day in hard gelatin capsules. Antemortem evaluative parameters for both species included grossly observable clinical signs, body weight and food consumption, clinical pathology (hematology, clinical chemistry, urinalysis), and ophthalmological examinations. Dogs also received electrocardiographic examinations. Postmortem evaluations in both species included complete necropsy, determination of major organ weights, and histopathological examination of specimens from approximately 50 organs and tissues. All rats and dogs survived to the scheduled termination of the studies and neither species exhibited evidence of VPP effects on appetite or body weight gain/maintenance. Ophthalmic examinations revealed occasional lens clouding in rats, but this occurred in all groups and was not attributable to VPP. Some clinical pathology parameters in both species were occasionally altered, but there was no evidence that this was dose-related. Electrocardiographic examinations in dogs revealed no VPP-associated changes. Mid- and high-dose male rats (but not females) had slightly reduced mean pituitary and kidney weight parameters, whereas mid- and high-dose females had slightly increased mean uterus:body weight ratios. There were no microscopic correlates for these minor changes. Ten percent to 20% of all female rats (but not males) exhibited corticomedullary mineralization of the kidney and gliosis of the optic nerve, and 10% to 20% of males (but not females) had thymic hemorrhage. Postmortem evaluations of dogs revealed no VPP-related effects on organ weights or either macro- or microscopic appearances of organs. The results of these studies provided no evidence of either local or systemic toxicity. Similarly, there was no evidence of neurotoxicity that might have been detected by the appearance of physical or behavioral changes during gross observations of animals. Although these results do not identify target organs for VPP toxicity, the no-observable-effect level and maximally tolerated dose are both greater than 16 mg/kg/day when administered to male and female rats and dogs for 8 consecutive weeks. Based upon food enhancement levels of VPP currently being evaluated, the resultant margin of safety (160) is substantial.
authors.affiliation: Product Development Laboratory, Calpis Co., Ltd. 11-10, 5-chome, Fuchinobe, Sagamihara, Kanagawa 229-0006, Japan. yasunori.nakamura@calpis.co.jp
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Izuki
authors.initials: I
authors.lastname: Bando
authors.forename: John H
authors.initials: JH
authors.lastname: Mennear
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Bernard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000097:blood; D002624:Chemistry, Clinical; D003318:Corneal Opacity / Q000175:diagnosis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D006405:Hematology / Q000379:methods; D006454:Hemoglobins / Q000032:analysis / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D051381:Rats; D012737:Sex Factors; D013045:Species Specificity; D013046:Specific Gravity / Q000187:drug effects; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods; D016482:Urinalysis; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D001786:Blood Glucose; D006454:Hemoglobins; D009842:Oligopeptides; C489032:isoleucyl-prolyl-proline; C489031:valyl-prolyl-proline; D009954:Ornithine Carbamoyltransferase; D005723:gamma-Glutamyltransferase; D001663:Bilirubin; D002118:Calcium