Phenytoin-induced connective tissue growth in the rat.

Rats were treated daily for 9 days with 100, 50, or 25 mg/kg phenytoin i.p. This treatment resulted in a significant increase in the thickness of the connective tissue capsules of the liver, spleen, and pancreas, and of the subepithelial connective tissue of the mesentery but not the epicardium or visceral pleura of the lung where exposure to the drug was via the vascular route. Many areas of connective tissue growth exhibited obvious proliferation of fibroblasts and in some areas contained seemingly large numbers of macrophages and an increase in vascularity. It was demonstrated by electron microscopy that the macrophages occasionally were seen in intimate contact with the fibroblasts. Our observations clearly showed that intraperitoneal exposure of visceral connective tissues of the rat to phenytoin rapidly resulted in a dose-related proliferation of that tissue. The presence of numerous macrophages leads to the suggestion that macrophage-derived growth factor could be responsible for the increased growth.