Inhibition of CYP1 by 7,8-Dehydrorutaecarpine and Its Methoxylated Derivatives
| 發布日期：2007-12-19 | 維護日期：2023-03-08
發布單位：
Inhibition of CYP1 by 7,8-Dehydrorutaecarpine and Its Methoxylated Derivatives
JEN-CHIH TSENG1,2, MING-JAW DON1, DAVID F. V. LEWIS3, SHU-YUN WANG1 AND YUNE-FANG UENG1,4*
1. National Research Institute of Chinese Medicine, 155-1, Sec. 2, Li-Nong St., Taipei 112, Taiwan (R.O.C.)
2. Department of Life Science, Chinese Culture University, Taipei 111, Taiwan (R.O.C.)
3. School of Biomedical and Molecular Sciences, University of Surrey, Guildfold GU2 7XH, U.K.
4. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan (R.O.C.)
ABSTRACT
7,8-Dehydrorutaecarpine was a potent inhibitor of both CYP1A1 and CYP1A2. The introduction of methoxyl group reduced CYP1A1 inhibition and enhanced the relative inhibition selectivity to either CYP1A2 or CYP1B1. Among the synthesized derivatives, 2-methoxy-7,8-dehydrorutaecarpine had the best selectivity of CYP1A2 inhibition. In contrast, the introduction of 4-methoxyl group decreased the IC50 values for CYP1B1 and had the best selectivity of CYP1B1 inhibition. Results of molecular modeling showed that a hydrogen bond was formed between the 2-methoxyl group of 2-methoxy-7,8-dehydrorutaecarpine and Thr113 residue of CYP1A2. 2-Methoxy-7,8-dehydrorutaecarpine was a mixed type inhibitor of CYP1A2 with the inhibition constants of 9.5 ± 2.6 and 6.7 ± 2.6 nM for CYP1A2 and CYP1A2-substrate complex, respectively. For the 2-methoxyl derivatives of 7,8-dehydrorutaecarpine and rutaecarpine, the change of 2-methoxyl to an 2-ethoxyl group decreased and increased the IC50 values for CYP1A1 and CYP1A2, respectively. Our results demonstrated that introduction of alkoxyl modification to a heterocyclic compound, 7,8-dehydrorutaecarpine could change inhibitory selectivity among CYP1 enzymes. These results may provide important information for the interaction between CYP1 members and their inhibitors with a core structure of 7,8-dehydrorutaecarpine.
Key words: CYP1, 7,8-dehydrorutaecarpine, inhibition, selectivity