Diamine oxidase, a plasma biomarker in rats to GI tract toxicity of oral fluorouracil anti-cancer drugs.
Diamine oxidase (DAO; EC 1.4.3.6), which catabolizes a variety of substrates including histamine and diamines, is the degradative enzyme of the catabolic pathway of polyamines found in high activity in the mature upper villus cells of the rat intestinal mucosa [Luk, G.D., Bayless, T.M., Baylin, S.B., 1983. Plasma post-heparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat. J. Clin. Invest. 71, 1308-1315; Wolvekamp, M.C.J., de Bruin, R.W.F., 1994. Diamine oxidase: an overview of historical, biochemical and functional aspects. Dig. Dis. 12, 2-14]. Rats were given 1-week repeated oral administration of anti-cancer drugs S-1, containing FT+CDHP+Oxo, and FCD, containing FT+CDHP, and the ameliorating effect of Oxo on the rat gastrointestinal (GI) tract toxicity from 5-FU was evaluated by measuring plasma DAO activity which is related to the enzyme located in the rat intestinal mucosa. Plasma DAO activity in the FCD-treated group was significantly less than that in the S-1-treated group while the jejunal mucosal area in the FCD group was significantly smaller than that in the S-1 group. In addition the histopathological findings in the FCD group showed villus atrophy in the jejunal mucosa which was not observed in the S-1 group. The degree of these findings correlated with the plasma DAO levels. Therefore, the protective effect of Oxo on 5-FU-induced GI tract toxicity was clarified by measuring plasma DAO activity in rats. In summary, DAO is a very sensitive plasma biomarker and will be useful for the quantitative evaluation of the small intestinal mucosal lesions induced by the anti-cancer drug, 5-FU, in rats.
Moriyama
Kenji
K
Drug Safety Research Laboratory, Taiho Pharmaceutical Co. Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan. k-moriyama@taiho.co.jp
Kouchi
Yasuhide
Y
Morinaga
Hidenobu
H
Irimura
Kenji
K
Hayashi
Taiji
T
Ohuchida
Akinobu
A
Goto
Tetsuhiro
T
Yoshizawa
Yasuo
Y
D000284:Administration, Oral; D006631:Amine Oxidase (Copper-Containing) / Q000097:blood*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood*; D001835:Body Weight / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007579:Jejunal Diseases / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009962:Orotate Phosphoribosyltransferase / Q000037:antagonists & inhibitors; D010094:Oxonic Acid / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D005641:Tegafur / Q000008:administration & dosage / Q000633:toxicity
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; C508179:FCD combination; D011725:Pyridines; D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D006631:Amine Oxidase (Copper-Containing); D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil