Celecoxib enhances the detoxification of diethylnitrosamine in rat liver cancer.
| Autor: | Salcido-Neyoy ME; Department of Cell Biology, Center of Research and Advanced Studies, National Politechnic Institute, Av. IPN No. 2508 Col. San Pedro Zacatenco, Mexico, DF, México., Sierra-Santoyo A, Beltrán-Ramírez O, Macías-Pérez JR, Villa-Treviño S |
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| Jazyk: | angličtina |
| Zdroj: | World journal of gastroenterology [World J Gastroenterol] 2009 May 21; Vol. 15 (19), pp. 2345-50. |
| DOI: | 10.3748/wjg.15.2345 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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