The relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia

The relationship between acute (<36 h) induction of apoptosis and longer-te rm (>72 h) intestinal histopathology was systematically investigated in viv o using p53 wild-type (+/+) and null (-/-) mice. Administration of the ente rotoxin fi-fluorouracil (5-FU) at either 40 or 400 mg/kg to BDF1 mice induc ed an acute p53-dependent apoptosis in the crypts of both small intestine a nd midcolon, Although the amount of apoptosis was of the same order of magn itude at its peak (24 h) at both doses, only 400 mg/kg 5-FU brought about h istopathological changes to the gut after 96 h, quantified as losses of cry pt and villus cellularity. Only after the administration of 400 mg/kg 5-FU were mitotic index and DNA synthesis significantly suppressed in both small intestinal and midcolonic crypts at 24 h. This correlated with a prolonged , p53-dependent expression of p21(waf-1/cip1.) In p53 null(-/-) mice, signi ficant reductions in both 5-FU-induced apoptosis and inhibition of cell cyc le progression allowed retention of crypt integrity 96 h after 5-FU. These results show that quantitative measures of acute apoptosis in vivo may not accurately predict subsequent pathological changes in the gut. Rather, p53- dependent inhibition of cell cycle progression, together with cell loss by apoptosis, caused a loss of crypt integrity. Importantly, the tissue toxici ty of 5-FU was genetically determined at a Locus (p53) separate from that d irectly associated with drug action.