Psoralen, a mechanism-based inactivator of CYP2B6.
Furanocoumarin compound psoralen (PRN) is a major active ingredient found in herbaceous plants. PRN has been used for the treatment of various dermal diseases in China. We evaluated the inhibitory effect of PRN on cytochrome P450 2B6 (CYP2B6) and found that PRN induced a time-, concentration-, and NADPH-dependent inactivation of CYP2B6 with the values of KI and kinact being 110.2 μM and 0.200 min(-1), respectively. Ticlopidine, a CYP2B6 substrate, prevented the enzyme from the inactivation induced by PRN. Exogenous nucleophile glutathione (GSH) and catalase/superoxide dismutase showed limited protection of CYP2B6 from the inactivation. The estimated partition ratio of the inactivation was approximately 400. GSH trapping experiments indicates that an epoxide or/and γ-ketoenal intermediate was formed in microsomal incubations with PRN. In summary, PRN was characterized as a mechanism-based inactivator of CYP2B6.
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Lin
L
Ji
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Dan
D
Lu
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Jiaojiao
J
Cao
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Liwei
L
Zheng
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: yingpeng1999@163.com.
Ying
Y
Peng
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA. Electronic address: jiang.zheng@seattlechildrens.org.
Jiang
J
Zheng
D065702:Cytochrome P-450 CYP2B6 / Q000737:chemistry / Q000378:metabolism*; D065686:Cytochrome P-450 CYP2B6 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005363:Ficusin / Q000737:chemistry / Q000494:pharmacology*; D013988:Ticlopidine / Q000378:metabolism / Q000494:pharmacology
D065686:Cytochrome P-450 CYP2B6 Inhibitors; D065702:Cytochrome P-450 CYP2B6; D005363:Ficusin; D013988:Ticlopidine
Cytochrome P450 2B6; Mechanism-based inactivation; Psoralen; Reactive metabolite