Dietary zinc supplementation and methotrexate-induced small intestinal mucositis in metallothionein-knockout and wild-type mice

Abstract

Background: Chemotherapy-induced small intestinal mucositis is a debilitating side effect of cancer chemotherapy and currently there are no effective therapies. Zinc (Zn), an essential trace element required for normal growth and development and tissue repair processes, may be a potential treatment strategy. Zn induces metallothionein (MT) which has been shown to sequester free radicals. The aim of this study was to determine the capacity for dietary Zn supplementation to ameliorate methotrexate (MTX)-induced intestinal mucositis. Methods: MT-knockout (MT-/-) and wild-type (MT+/+) mice were fed either a 10 mg/kg (control) or 400 mg/kg diet (high Zn) for 7 days and intestinal mucositis was induced by a single injection of MTX (500 mg/kg) subcutaneously. Mice were sacrificed at 24 and 72 h (n=8/timepoint/genotype) after the MTX injection while continuing their respective diets. Daily weights were recorded and gut tissues were collected for histology, MT levels and myeloperoxidase (MPO) activity. Results: The duodenum and jejunum were significantly (p<0.05) damaged at the 500 mg/kg MTX dose compared to 300 and 400 mg/kg MTX doses. Dietary Zn supplementation did not induce gut MT in MT+/+ mice nor ameliorate MTX-induced gut damage in either MT+/+ or MT-/- mice. However, MT-/- mice had markedly (p<0.05) higher histological severity scores and MPO activity compared to MT+/+ mice, irrespective of dietary Zn. Conclusions: Dietary Zn supplementation did not ameliorate MTX-induced small bowel damage, possibly signifying a deficiency in induction of MT by Zn. However, the presence of MT was able to reduce histological damage and neutrophil infiltration caused by MTX in the gut.