Effect of malnutrition on methotrexate toxicity and tissue levels of dihydrofolate reductase in the rat.
The effect of malnutrition on the toxicity of methotrexate (MTX) and the dihydrofolate reductase (DHFR) content of the liver, small intestinal mucosa, kidney, and bone marrow of male Sprague-Dawley rats was studied. Malnutrition was induced by reducing the daily intake of chow to one third for 14 days. A single ip treatment with MTX was lethal to three of nine rats at a dose of 37.5 mg/kg and to three of five rats at a dose of 50.0 mg/kg but caused only transient weight loss to similarly treated full-fed, age-matched controls. Although the body weights and absolute tissue weights were reduced in malnourished rats, only the liver and small intestinal mucosa were smaller relative to their respective body weights. The cellular DHFR content of liver and bone marrow from malnourished rats was lower than that from the controls, although in terms of the content per gram of tissue, there was no significant change. While the total DHFR in malnourished rat tissues was significantly lower than that for the controls, only the total-liver DHFR was lower relative to the body weight. The increased toxicity of MTX to malnourished rats may be related to the DHFR levels in the liver and bone marrow.
D000818:Animals; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D009748:Nutrition Disorders / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate