5-Fluorouracil-induced intestinal toxicity: what determines the severity of damage to murine intestinal crypt epithelia?
To elucidate the relationship between 5-fluorouracil (5-FU) distribution and 5-FU-induced apoptosis and/or cell cycle arrest, microautoradiography was applied to murine intestinal crypts exposed to [14C] 5-FU by intravenous infusion. The histologic location of apoptotic cells in the crypt did not correlate to that of 5-FU. The temporal profiles of apoptotic and/or mitotic indexes corresponded to those of orally administered 5-FU in a previous study. Two cell cycle-related proteins, p21(WAF/Cip1) and bax, were also investigated in the present study. With time, p21(WAF/Cip1)-positive nuclei apparently migrated up the crypt. Bax-positive cytoplasm was observed throughout the crypt epithelial cells, accompanied by the occurrence of apoptosis, and remained until 48 h when the control level recovered. The findings demonstrate that 5-FU mainly exerts an apoptotic effect and/or cell cycle arrest by systemic exposure, and p21 and bax expression determine an individual cell's fate.
Inomata
Akira
A
Department of Preclinical Science, Nippon Roche Research Center, Kajiwara 200, Kamakura-city, Kanagawa 247-8530, Japan. akira.inomata@roche.com
Horii
Ikuo
I
Suzuki
Katsushi
K
D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001345:Autoradiography; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D004386:Duodenum / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D012007:Rectum / Q000473:pathology; D013997:Time Factors; D051028:bcl-2-Associated X Protein
D000963:Antimetabolites; C494827:Bax protein, mouse; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D015689:Oncogene Protein p21(ras); D005472:Fluorouracil