Microvascular perturbations in rats receiving the maximum tolerated dose of methotrexate or its major metabolite 7-hydroxymethotrexate

Methotrexate (MTX) is a clinically important cytostatic antifolate. The stu dy describes the acute effects of maximum tolerated doses of MTX or its maj or metabolite 7-hydroxymethotrexate (7-OH-MTX) on the ultrastructure of rat liver and kidneys. The ultrastructural changes in rats receiving MTX or 7- OH-MTX were, in principle, indistinguishable and their severity and extensi on increased with time of survival or doses of medication. All lesions were focal, microvascular, or parenchymal. Microvascular changes were more seve re in nature when blood cells were present. The endothelial cells were swol len with loss of pinocytotic vesicles, their luminal plasma membrane formed blebs or were disrupted. Partly detached endothelial cells or deendothelia lized areas, various types of white blood cells, in particular, neutrophil granulocytes, were observed in the microcirculation. Single platelets or sm all platelet aggregates were found either in the lumen or adhering to deend othelialized areas of injured endothelial cells. Hepatocytes exhibited stea tosis, edema, and manifest single cell necrosis. There were also nuclear ch anges, marked proliferation of smooth endoplasmatic reticulum, increased am ounts of intracellular lipid vacuoles, and a decrease in glycogen particles in hepatocytes. The kidney presented the major changes in the tubules and in the interstitial part. MTX and 7-OH-MTX acute toxicity may primarily be related to microvascular perturbation.