title: Evaluation of the RBC Pig-a and PIGRET assays using single doses of hydroxyurea and melphalan in rats.
abstract: To evaluate the suitability of the rat Pig-a assay on reticulocytes (PIGRET assay) as a short-term test, red blood cell (RBC) Pig-a and PIGRET assays after single doses with hydroxyurea (HU) and melphalan (L-PAM) were conducted and the results of both assays were compared. HU was administered once orally to male SD rats at 250, 500 and 1000mg/kg, and both assays were conducted using peripheral blood withdrawn from the jugular vein at 1, 2 and 4 weeks after dosing. L-PAM was administered at 1.25, 2.5 and 5mg/kg in the same manner. L-PAM produced significant dose-dependent increases in mutant frequencies in the PIGRET assay after single oral doses, but did not produce dose-dependent increases in mutant frequencies in the RBC Pig-a assay. These results suggest that the PIGRET assay is more sensitive for the evaluation of the mutagenic potential of L-PAM than the RBC Pig-a assay. In contrast, HU, a clastogenic but not DNA-reactive compound, gave negative results in both assays. The results with these 2 chemicals indicate that the single-dose PIGRET assay in rats has the potential to properly detect DNA-reactive compounds that directly cause DNA damage in a short-term assay.
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka 554-0022, Japan. Electronic address: hideki-adachi@ds-pharma.co.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamada
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000187:drug effects*; D006918:Hydroxyurea / Q000633:toxicity*; D008297:Male; D008558:Melphalan / Q000633:toxicity*; D008565:Membrane Proteins / Q000235:genetics*; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000187:drug effects*
chemical_list: D008565:Membrane Proteins; D009153:Mutagens; C080086:phosphatidylinositol glycan-class A protein; D008558:Melphalan; D006918:Hydroxyurea
keywords: Hydroxyurea; Melphalan; PIGRET assay; RBC Pig-a assay; Rat