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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. © 2009 The WJG Press and Baishideng. All rights reserved.
Celecoxib; Chemoprevention; Cytochromes P450; Denitrosation; Diethylnitrosamine; Hepatocarcinogenesis acetaldehyde; celecoxib; cytochrome P450 1A1; cytochrome P450 2A; cytochrome P450 2B1; cytochrome P450 2B2; cytochrome P450 2E1; diethylnitrosamine; nitrite; proadifen; animal experiment; animal model; article; cancer model; cancer prevention; controlled study; detoxification; drug efficacy; drug mechanism; drug protein binding; enzyme activity; enzyme inhibition; enzyme regulation; in vitro study; liver cancer; liver microsome metabolism; long term care; male; nonhuman; protein expression; rat; Sprague Dawley rat; treatment duration; Animals; Aryl Hydrocarbon Hydroxylases; Cyclooxygenase Inhibitors; Diethylnitrosamine; Liver Neoplasms, Experimental; Male; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides
Celecoxib enhances the detoxification of diethylnitrosamine in rat liver cancer
acetaldehyde, 75-07-0; celecoxib, 169590-42-5; cytochrome P450 2B1, 330207-10-8; cytochrome P450 2B2, 331462-97-6; diethylnitrosamine, 55-18-5; nitrite, 14797-65-0; proadifen, 302-33-0, 62-68-0; Aryl Hydrocarbon Hydroxylases, 1.14.14.1; Cyclooxygenase Inhibitors; Diethylnitrosamine, 55-18-5; Pyrazoles; Sulfonamides; celecoxib, 169590-42-5
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%2bCXB-treated group (DEN%2bCXB), 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%2bCXB 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%2bCXB group. The observed increase in the enzymatic activities in the DEN%2bCXB 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. © 2009 The WJG Press and Baishideng. All rights reserved.
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