Inhibition of CYP1 by 7,8-dehydrorutaecarpine and its methoxylated derivatives

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Title:	Inhibition of CYP1 by 7,8-dehydrorutaecarpine and its methoxylated derivatives
Authors:	Tseng, Jen-Chin Don, Ming-Jaw Lewis, David F. V. Wang, Shu-Yun Ueng, Yune-Fang
Contributors:	生科系
Keywords:	CYP1 7,8-dehydrorutaecarpine inhibition selectivity
Date:	2007
Issue Date:	2009-11-09 09:09:40 (UTC+8)
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 Thr(113) 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.
Relation:	OF FOOD AND DRUG ANALYSIS Volume: 15 Issue: 4 Pages: 480-487
Appears in Collections:	[生命科學系] 期刊論文

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