| Autor: |
Liu J; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Pham PT; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Skripnikova EV; Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States., Zheng S; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.; RCMI Cancer Research Center, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Lovings LJ; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Wang Y; College of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, P. R. China., Goyal N; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Bellow SM; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Mensah LM; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Chatters AJ; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Bratton MR; Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States., Wiese TE; Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States., Zhao M; College of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, P. R. China.; Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University , Kaohsiung 807, Taiwan., Wang G; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.; RCMI Cancer Research Center, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States., Foroozesh M; Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States. |
| Abstrakt: |
In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a K(I) value of 0.44 μM. With a 5 min preincubation in the presence of NADPH, 0.01 μM 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a K(i) of 0.39 μM, 155- and 52-fold lower than its K(i) values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethylcoumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 μM, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethylcoumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 μM. Thus, using 7,8-pyrano-4-trifluoromethylcoumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents. |
