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ToxSci Advance Access published online on April 7, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn071
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EVIDENCE THAT THE ANTICARCINOGENIC EFFECT OF CAFFEIC ACID PHENETHYL ESTER IN THE RESISTANT HEPATOCYTE MODEL INVOLVES MODIFICATIONS OF CYTOCHROME P450

Olga Beltrán-Ramírez*, Leticia Alemán-Lazarini*, Martha Salcido-Neyoy*, Sergio Hernández-García*, Samia Fattel-Fazenda*, Evelia Arce-Popoca*, Jaime Arellanes-Robledo*, Rebeca García-Román*, Patricia Vázquez-Vázquez{dagger}, Adolfo Sierra-Santoyo{dagger} and Saúl Villa-Treviño*

* Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México 14, DF, CP 07360, México, obeltran{at}cell.cinvestav.mx, letyaleman2{at}yahoo.com.mx, msalcido{at}cell.cinvestav.mx, sergio{at}cell.cinvestav.mx, asaib2001{at}yahoo.com.mx, eveli{at}mexico.com, jarellan{at}cell.cinvestav.mx, bky_gr{at}yahoo.com, svilla{at}cell.cinvestav.mx {dagger} Sección Externa de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Av. IPN No. 2508 Col. San Pedro Zacatenco, México 14, DF, CP 07360, México. patyva_21{at}yahoo.com.mx, asierra{at}cinvestav.mx

Corresponding Author: Saúl Villa-Treviño, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV), Departamento de Biología Celular, Av. IPN No. 2508 Col. San Pedro Zacatenco, México 14, DF, CP 07360, México, telephone: (52) 55 57473993. Fax (52) 55 57473393; E-mail: svilla{at}cell.cinvestav.mx.

Received October 3, 2007; revision received March 28, 2008; accepted March 28, 2008


  Abstract

Caffeic acid phenethyl ester (CAPE), a natural component of propolis, shows anti-carcinogenic 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 h, 24 h, and 25 d after DEN administration. Liver damage was determined by histology with hematoxylin and eosin, measurement of total CYP levels and enzyme activity, and {gamma}-glutamyltranspeptidase-positive (GGT+) staining of hepatocyte foci . CAPE administration prevented DEN-induced necrosis at 24 h. It also decreased EROD, MROD, and PROD activity at 12 h after its administration and EROD and MROD activity 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 cytochrome P450 isoforms involved in the activation of DEN, such as CYP1A1/2, 2B1/2. These findings describe an alternative mechanism for understanding the ability of CAPE to protect against chemical hepatocarcinogenesis.

Key Words: Chemoprevention; Cytochrome P450; DEN metabolism; Hepatocarcinogenesis.


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