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The Journal of Nutrition Vol. 127 No. 5 May 1997, pp. 770-776
Copyright ©1997 by the American Society for Nutritional Sciences

Vitamin A Deficiency Exacerbates Methotrexate-Induced Jejunal Injury in Rats

Manuscript received 3 September 1996. Initial reviews completed 28 October 1996. Revision accepted 16 December 1996.

Rosemary A. Warden, Rhiannon S. Noltorp*, J. Lynn Francis, Peter R. Dunkley, and Edward V. O'Loughlin*,

Faculty of Medicine and Health Sciences, The University of Newcastle, Callaghan, NSW, Australia 2308 and * Department of Paediatrics, John Hunter Hospital, New Lambton Heights, NSW, Australia 2305

Two studies were conducted to investigate whether vitamin A-deficient rats were more susceptible to intestinal injury caused by methotrexate (MTX), since vitamin A deficiency alone causes only mild changes to jejunal structure and function. Weanling male rats were fed a vitamin A-deficient diet (-VA) for 40-42 d and compared to rats either pair-fed (PF) or with free access (+VA) to the same diet. Drinking water of PF and +VA rats was supplemented with 37.5 µg (Study 1) or 75 µg (Study 2) vitamin A (Rovimix A 500W)/d. Rats in each group received MTX (-VAMTX, PFMTX, +VAMTX) or vehicle. MTX administration reduced intestinal mucosal wet weight, protein and DNA concentrations, and sucrase and maltase activities in -VA and PF rats (P < 0.02). In Study 1, -VAMTX rats developed a severe jejunal enteropathy and had a higher incidence of diarrhea (P < 0.005), greater weight loss (P < 0.005), more disruption of villus architecture (P < 0.0001) and lower disaccharidase activity (P < 0.007) than PFMTX rats. Similar results were observed in Study 2. Liver retinol concentration (but no other variable) was greater in rats receiving 75 µg vitamin A/d (P < 0.001) than in those receiving 37.5 µg/d. The interaction of vitamin A deficiency and small intestinal injury may explain the efficacy of vitamin A supplementation in preventing childhood diarrheal disease mortality in developing countries, and highlights the need for ensuring adequate vitamin A status in people worldwide with diseases and/or treatments which may injure the gastrointestinal tract.

Key words: vitamin A deficiency, diarrhea, rats, jejunal injury, methotrexate.




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