Protocatechuic acid suppresses diethylnitrosamine-induced hepatic preneoplastic lesions by inhibiting phase I enzymes, reducing cell proliferation, and promoting apoptosis

Protocatechuic acid (PCA) is a phenolic compound naturally occurring in various plants. Although numerous studies have reported on its various biological activities, information on the anti-carcinogenic potential and its molecular mechanisms in animal models has never been conclusively determined. Therefore, this study aimed to study the inhibitory effect of PCA against diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis. Rats received three intraperitoneal injections of 100 mg kg^-1 body weight of DEN to initiate hepatic preneoplastic lesions, and glutathione S-transferase placental form (GST-P)-positive foci were used as the end-point marker. Rats were treated with PCA at 40 mg kg^-1 body weight by oral gavage administration for 15 weeks to study its chemopreventive effect on the early stages of hepatocarcinogenesis. PCA treatment decreased the number and the area of hepatic GST-P-positive foci in DEN-induced rats. It inhibits the activity of cytochrome P450 reductase and reduces the expression of cytochrome P450 2E1 protein. It also suppresses cell proliferation by down-regulation of Cyclin D1 expression. Additionally, it induces apoptosis, as indicated by the up-regulation of pro-apoptotic genes, Bax and Bad, in DEN-induced rats. These findings suggest that PCA is an anti-cancer agent that inhibits hepatocarcinogenesis in DEN-treated rats.