Induction of colon tumorigenesis by glutathione depletion in p53-knock-out mice.

In order to examine the role of glutathione (GSH), a key cellular antioxidant, on spontaneous tumor development, we tested the effects of buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, and 1,2-oxothiazolidine-4-carboxylic acid (OTCA), a cysteine and GSH precursor, on tumor incidence and spectrum in p53 nullizygous (p53-/-) transgenic mice. Mice were randomly assigned to three groups: control (no treatment), BSO (20 mM in drinking water) or OTCA (6 g/kg in the diet) (n=30 per group). After 10 weeks, GSH levels were decreased 29-88% in all tissues except liver and brain in BSO-treated mice, while no changes were observed in most tissues from OTCA-treated animals. Mice in all groups showed similar survival patterns as well as incidence of the most commonly observed tumors: i.e., lymphomas (80%) and other tumors (38%). However, a 5-fold increase in incidence of colonic tumors (from 4-20%) was observed in the BSO-treated group, suggesting that GSH deficiency and loss of p53 function play contributory roles in colon carcinogenesis.