Vitamin A Deficiency Exacerbates Methotrexate-Induced Jejunal Injury in Rats

Abstract

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.