Brief Articles
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World J Gastroenterol. May 21, 2009; 15(19): 2345-2350
Published online May 21, 2009. doi: 10.3748/wjg.15.2345
Celecoxib enhances the detoxification of diethylnitrosamine in rat liver cancer
Martha Estela Salcido-Neyoy, Adolfo Sierra-Santoyo, Olga Beltrán-Ramírez, José Roberto Macías-Pérez, Saúl Villa-Treviño
Martha Estela Salcido-Neyoy, Olga Beltrán-Ramírez, José Roberto Macías-Pérez, Saúl Villa-Treviño, Department of Cell Biology, Center of Research and Advanced Studies of the National Politechnic Institute, Mexico, DF, CP 07360, México
Adolfo Sierra-Santoyo, External Section of Toxicology, Center of Research and Advanced Studies of the National Politechnic Institute, Mexico, DF, CP 07360, México
Author contributions: Salcido-Neyoy ME, Sierra-Santoyo A and Villa-Treviño S designed the research; Salcido-Neyoy ME performed the majority of the experiments and wrote the manuscript; Beltrán-Ramírez O and Macías-Pérez JR provided analytical tools and were also involved in editing the manuscript; Sierra-Santoyo A and Villa-Treviño S contributed to the editing of the manuscript.
Correspondence to: Saúl Villa-Treviño, MD, PhD, Department of Cell Biology, Center of Research and Advanced Studies of the National Politechnic Institute, Av. IPN No. 2508 Col. San Pedro Zacatenco, Mexico, DF, CP 07360, México. svilla@cell.cinvestav.mx
Telephone: +52-55-57473993
Fax: +52-55-57473393
Received: February 7, 2009
Revised: April 17, 2009
Accepted: April 24, 2009
Published online: May 21, 2009
Abstract

AIM: To study the effect of celecoxib (CXB) on diethylnitrosamine activation through the regulation of cytochrome P450 in a hepatocarcinogenesis model.

METHODS: Six-week-old male Sprague-Dawley rats were randomly divided into five groups, a non-treated group (NT), a diethylnitrosamine-treated group (DEN), a DEN+CXB-treated group (DEN+CXB), and CXB 8 d-treated and CXB 32 d-treated groups. The effects of celecoxib on the enzymatic activities of CYP1A1, 2A, 2B1/2, and 2E1 were assessed in hepatic microsomes 24 h after DEN administration. Changes in CYP1A1 and CYP2B1/2 protein expression were also evaluated. The rate of DEN metabolism was measured by the production of the deethylation metabolite acetaldehyde, and the denitrosation metabolite nitrite.

RESULTS: DEN+CXB administration produced a significant increase in the enzymatic activities of CYP2B1/2 and 1A1, whereas it did not change the activities of CYP2A and 2E1, compared to that of the DEN group. CXB treatment for eight days did not produce a significant effect on enzymatic activity when compared to the NT group; however, when it was administered for prolonged times (CXB 32 d group), the enzymatic activities were increased in a similar pattern to those in the DEN+CXB group. The observed increase in the enzymatic activities in the DEN+CXB group was accompanied by an increase in the CYP2B1/2 protein levels; no changes were observed in the levels of CYP1A1. In vitro, CXB increased the denitrosation of DEN, a pathway of metabolic detoxification. The addition of SKF-525A, a preferential inhibitor of CYP2B, abrogated the denitrosation of DEN.

CONCLUSION: These results suggest that the mechanism of action of CXB involves enhancement of the detoxification of DEN by an increasing denitrosation via CYP2B1/2.

Keywords: Hepatocarcinogenesis; Chemoprevention; Diethylnitrosamine; Denitrosation; Celecoxib; Cytochromes P450