Hepatocellular tumor induction in heterozygous p53-deficient CBA mice by a 26-week dietary administration of kojic acid

Abstract

In order to evaluate the tumorigenic potential of kojic acid (KA), used as a food additive for preventing enzymatic browning of crustaceans and a cosmetic agent for the purpose of skin whitening, heterozygous p53-deficient CBA [p53(+/-)] mice, which are recognized as useful for detecting genotoxic carcinogens, and wild-type littermates [p53(+/+) mice] were fed diet containing 0, 1.5, and 3% KA for 26 weeks. KA induced diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells with decreased serum thyroxine levels in both p53(+/-) and p53(+/+) mice, but caused no thyroid tumors. In the liver, the incidence of altered hepatocellular foci was significantly increased at 1.5 and 3% in p53(+/-) and 1.5% in p53(+/+) mice, and that of hepatocellular adenomas was increased at 1.5 and 3% in p53(+/-) and 3% in p53(+/+) mice. p53(+/-) mice thus appeared to be more susceptible in terms of the tumorigenic dose of KA with a greater prevalence of hepatic proliferative lesions. The results of the present study indicate tumorigenic potential of KA in the liver, but not thyroid follicular epithelial cells in CBA mice and a contribution of genotoxicity on hepatocellular tumor development cannot be ruled out.