Evidence that the Anticarcinogenic Effect of Caffeic Acid Phenethyl Ester in the Resistant Hepatocyte Model Involves Modifications of Cytochrome P450

Abstract

Caffeic acid phenethyl ester (CAPE), a natural component of propolis, shows anticarcinogenic properties in the modified resistant hepatocyte model when administered before initiation or promotion of hepatocarcinogenesis process; however, information about the mechanism underlying this chemoprotection is limited. The aim of this work was to characterize the effect of CAPE on cytochrome P450 (CYP), which is involved in diethylnitrosamine (DEN) metabolism during the initiation stage of chemical hepatocarcinogenesis. Male Fischer-344 rats were treated as in the modified resistant hepatocyte model. Liver samples were obtained at four different times: at 12 h after pretreatment with CAPE and at 12 and 24 h and 25 days after DEN administration. Liver damage was determined by histology with hematoxylin and eosin, measurement of total CYP levels and enzyme activity, and gamma-glutamyl transpeptidase-positive (GGT+) staining of hepatocyte foci. CAPE administration prevented DEN-induced necrosis at 24 h. It also decreased O-dealkylation of 7-ethoxy-resorufin (EROD), O-dealkylation of 7-methoxyresorufin (MROD), and 7-pentoxy-resorufin activities at 12 h after its administration and EROD and MROD activities at 12 h after administration of DEN. CAPE treatment decreased GGT+ foci by 59% on day 25. Our results suggest that CAPE modifies the enzymatic activity of CYP isoforms involved in the activation of DEN, such as CYP1A1/2 and CYP2B1/2. These findings describe an alternative mechanism for understanding the ability of CAPE to protect against chemical hepatocarcinogenesis.

Toxicity of mycotoxins to honeybees and its amelioration by propolis

“…Propolis treatment has been shown to increase activities of a range of P450s, including pentoxyresorufin depentylase, and ethoxycoumarin deethylase (Siess et al 1996). More recently, Beltrán-Ramírez et al (2008) reported that caffeic acid phenethyl ester, a common constituent of propolis, can modify expression of multiple P450s to inhibit the activation of diethylnitrosamine in rats. To some extent, it is remarkable that the body of knowledge relating to the biochemical activity of propolis in human health is substantially larger than that relating to the biochemical activity of propolis in honeybee health; a greater understanding of the multiple roles of propolis in the life of the honeybee can be gained by further study of the ways in which it is processed and metabolized.…”

Cancer Prevention Mediated by Caffeic Acid Phenethyl Ester Involves Cyp2b1/2 Modulation in Hepatocarcinogenesis

“…Chemoprotective agents regulate the expression of drug-metabolizing enzymes because their activity may contribute to the sensitivity of different individuals to develop cancer (Moon et al 2006;Ragin et al 2010). Confirming the effects of CAPE on a specific CYP will help us elucidate the mechanism of CAPE as a chemoprotective agent in the modified resistant hepatocyte model of hepatocarcinogenesis, which may become a referent model (Bai et al 2011;Beltran-Ramirez et al 2008;Beltran-Ramirez et al 2010;Carrasco-Legleu et al 2006). Different effects have been observed for CAPE as a chemoprotective agent.…”

In vitro antiproliferative/cytotoxic activity on cancer cell lines of a cardanol and a cardol enriched from Thai Apis mellifera propolis

“…The mechanism of how CAPE inhibits the growth of cancer cell lines has been widely studied. In addition, CAPE has been reported to only be cytotoxic to cancer cell lines and not to normal cells in vitro [20,21], and this is additionally supported by the results from the systemic in vivo administration of CAPE [22]. Other than CAPE, artepillin C from Brazilian green propolis was reported to almost completely suppress the growth of human neurofibromatosis tumor xenografts in mice by blocking the oncogenic PAK1 signaling pathway [23].…”