中国药理学与毒理学杂志2012，Vol.26Issue(4)：522-528,7.DOI:10.3867/j.issn.1000-3002.2012.04.010
补骨脂素和异补骨脂素对体外细胞色素P450酶活性的抑制和诱导作用
Evaluation of cytochrome P450 inhibition and induction by psoralen and isopsoralen in vitro
摘要
Abstract
OBJECTIVE To evaluate inhibitory and induetory activities of psoralen ( PSO) and isopsoralen (IPSO) on cytochrome P450 (CYP) isoforms. METHODS PSO or IPSO was incubated with human liver microsomes ( HLM) or rat liver microsomes ( RLM) for 30 min in the presence of NADPH and CYP probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Phenacetin-O-deethylation, tolbutamide methyl hydroxylation, mephenytoin 4-hydroxyl-ation, dextromethorphan-O-demethylation and midazolam 1'-hydroxylation were used as marked reactions to measure enzyme activities. The relative activities of CYP isoforms were determined by analyzing the formation of the probe metabolites in the incubation system. IC50 was calculated to assess the inhibitory potency of PSO and IPSO on these CYP isoenzymes. To evaluate CYP induction effect, PSO, IPSO or known CYP inducers were incubated with sandwich-cultured rat hepatocytes for 72 h, followed by 1 h incubation of the hepatocytes with CYP1A or 3A substrates to measure the relative activities of CYP isoforms. The enzyme activities in PSO and IPSO groups were compared with those of known inducers to assess the induction potentials. RESULTS PSO and IPSO showed a strong inhibitory activity'on CYP1A2 in both HLM and RLM incubations in vitro. IC50 of PSO and IPSO in HLM was 0. 17 and 0. 13 μmol·L-1, 0. 47 and 0. 36μmol·L-1 in RLM, respectively. A moderate inhibitory activity of PSO and IPSO on CYP2D6 in HLM was also observed, with IC50 of 3.59 and 9.51 μmol·L-1. PSO and IPSO 100 μmol·L-1 demonstrated inductory activity on rat CYP3A. After incubation with rat hepatocytes for 72 h, PSO and IPSO increased CYP3A activity 1.18 and 0. 96 times, respectively. CONCLUSION PSO and IPSO are strong inhibitors of CYP1A2 but moderate inhibitors for CYP2D6. They also show induction potency on rat CYP3A.关键词
补骨脂素类/异补骨脂素/细胞色素类/药物相互作用/微粒体,肝Key words
psoralens/isopsoralen/cytochromes/drug interactions/microsomes, liver分类
医药卫生引用本文复制引用
钟玉环,沈国林,原梅,刘万卉,李桦..补骨脂素和异补骨脂素对体外细胞色素P450酶活性的抑制和诱导作用[J].中国药理学与毒理学杂志,2012,26(4):522-528,7.基金项目
国家"重大新药创制"科技重大专项(2012ZX09301003) （2012ZX09301003）
国家"重大新药创制"科技重大专项(2008ZXJ09006-001) （2008ZXJ09006-001）
