Cinnamyl anthranilate causes coinduction of hepatic microsomal and peroxisomal enzymes in mouse but not rat

Cinnamyl anthranilate is a synthetic food flavoring and fragrance agent, formerly used at low levels. Although it is not genotoxic, very high doses have been shown to cause liver tumors in mice but not rats. In this report we characterize hepatic changes brought about by cinnamyl anthranilate in rats and mice. Groups of male CD1 mice and Fischer 344 rats received 0, 100, or 1000 mg/kg cinnamyl anthranilate by intraperitoneal injection daily for 3 days. After euthanization on the 4th day, plasma lipids and relative liver weight, tissue DNA, the peroxisome marker CN(-)-insensitive palmitoyl-CoA oxidation, cytochrome P450, microsomal lauric acid hydroxylation, aminopyrine N-demethylase and ethoxyresorufin O-deethylase, bilirubin UDP-glucuronosyltransferase, microsomal and cytosolic epoxide hydrolase, and the peroxisome/mitochondria ratio in liver sections were monitored. In mice a pattern of change pointing to peroxisomal proliferation was seen at both doses of cinnamyl anthranilate, but in rats fewer and smaller changes were seen with little or no evidence of peroxisomal proliferation at the doses used. Groups of male CD1 mice were given 0-200 mg/kg cinnamyl anthranilate daily for 3 days. At doses of 20 mg/kg and above, there were dose-dependent increases in relative liver weight, total cytochrome P450, and CN(-)-insensitive palmitoyl-CoA oxidation. The hepatic effects of cinnamyl anthranilate are apparently due to the intact ester, since neither its expected metabolites alone nor an equimolar mixture of the hydrolysis products, cinnamyl alcohol and anthranilic acid, had any significant effect on the weight or marker enzyme content of mouse liver. The data are discussed in relation to the species specificity of the hepatocarcinogenicity of cinnamyl anthranilate and to metabolic studies in rats and mice. It is suggested that in mice, peroxisomal proliferation occurs only at doses high enough to prevent complete metabolic hydrolysis.