Response of the rat small-intestine epithelium to methotrexate

We studied jejunal epithelial structure and function in rats 24, 48, 96, and 192 hours after a single intravenous injection of methotrexate (MTX) 30 mg/kg. The acute effect of the drug on the gut at 24 and 48 hours was characterised, as expected, by reduced mitoses in crypts, shortened villi, and depressed activity of thymidine kinase (an enzyme normally confined to intestinal crypt cells). At 96 hours, when MTX was no longer detectable in serum, the intestine had entered a proliferative phase characterised by increased crypt mitoses, accelerated migration of enterocytes along villi, and the presence on villi of epithelial cells with the enzyme profile of crypt cells, decreased disaccharidase, alkaline phosphatase, and Na+-K+ATPase activities and increased thymidine kinase activity. Although the enzyme data suggested that enterocyte maturation was defective during this proliferative phase, glucose-stimulated Na+ transport, normally a function of fully differentiated villus cells, was normal at 96 hours. Measured both in Ussing chambers and in suspensions of enterocytes isolated from villi, Na+ transport responded normally to glucose at 96 hours, although the response had been significantly depressed at 24 hours. These findings cannot be attributed to MTX-induced malnutrition, as all comparisons included pair-fed controls. We conclude that, in the MTX-induced malnutrition, as all comparisons included pair-fed controls. We conclude that, in the small intestine under conditions of altered epithelial renewal, some components of enterocyte function may be affected more than others. Comparing the present experimental model with another intestinal disorder, acute viral enteritis, in which proliferative activity is excessive, it is clear that the nature of the original intestinal injury is a significant determinant of the pattern of enterocyte response.