Vitamin A deficiency exacerbates methotrexate-induced jejunal injury in rats.
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 microg (Study 1) or 75 microg (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 microg vitamin A/d (P < 0.001) than in those receiving 37.5 microg/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.
Warden
R A
RA
Faculty of Medicine and Health Sciences, The University of Newcastle, Callaghan, NSW, Australia.
Noltorp
R S
RS
Francis
J L
JL
Dunkley
P R
PR
O'Loughlin
E V
EV
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001361:Avitaminosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D001835:Body Weight / Q000502:physiology; D004247:DNA / Q000032:analysis; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology / Q000503:physiopathology; D004187:Disaccharides / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005527:Food, Fortified; D015994:Incidence; D007413:Intestinal Mucosa / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D007579:Jejunal Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D007583:Jejunum / Q000187:drug effects / Q000473:pathology*; D008099:Liver / Q000737:chemistry; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013393:Sucrase / Q000032:analysis; D014801:Vitamin A / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000627:therapeutic use; D000520:alpha-Glucosidases / Q000032:analysis
D000964:Antimetabolites, Antineoplastic; D004187:Disaccharides; D014801:Vitamin A; D004247:DNA; D000520:alpha-Glucosidases; D013393:Sucrase; D008727:Methotrexate