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目的:研究双环醇对大鼠肝微粒体CYP450同工酶及Ⅱ相酶的诱导或抑制作用。方法:大鼠灌胃给予双环醇200mg·kg-1·d-1,连续给药3d,测定CYP450 6种主要同工酶(CYP2D,2C6,2C,3A,1A2,2E1)选择性底物的代谢速率及Ⅱ相酶[尿苷二磷酸葡萄糖醛酸转移酶(UDPGT)、谷胱甘肽巯基转移酶(GST)及谷胱苷肽还原酶(GR)]的酶活性。结果:双环醇10μmol·L-1与正常大鼠肝微粒体体外温孵后,对CYP3A,1A2,2E1和2C同工酶选择性底物氨苯砜、非那西丁、氯唑沙宗和奥美拉唑的代谢速率有一定抑制作用,分别为对照组的19%,40%,42%和78%,其中以对CYP3A底物氨苯砜的抑制作用最为明显。双环醇灌胃给药3d后,对大鼠肝微粒体CYP2C和CYP2D有不同程度的抑制作用,Km和Vmax分别为对照组的32%和57%,对CYP2E1的酶活性有轻度诱导作用,Km和Vmax为对照组的170%。双环醇对Ⅱ相酶UDPGT,GST,GR也有轻度诱导作用(酶活性分别为对照组的129%,121%和117%)。结论:双环醇对CYP450和Ⅱ相酶具有一定的调控作用,其对代谢性药物相互作用的潜在影响值得关注。
OBJECTIVE: To study the induction or inhibition of CYP450 and phase Ⅱ enzymes induced by bicyclol in rat liver microsomes. METHODS: Bicyclol 200 mg · kg-1 · d-1 was intragastrically administered to rats for three consecutive days. The CYP450 selective substrates (CYP2D, 2C6, 2C, 3A, 1A2 and 2E1) Metabolic rate and enzyme activities of phase Ⅱ enzymes [UDPGT, GST and GR]. Results: After incubating 10 micromol·L -1 bicyclol with normal rat liver microsomes in vitro, the activities of CYP3A, 1A2, 2E1 and 2C isozymic substrates such as dapsone, phenacetin, Omeprazole has a certain degree of inhibition of the metabolic rate, respectively, 19%, 40%, 42% and 78% of the control group, of which CYP3A substrate dapsone most obvious inhibition. Cyclosporine administered intragastrically for 3 days had inhibitory effects on CYP2C and CYP2D in rat liver microsomes to varying degrees, with Km and Vmax being 32% and 57% of those in the control group, respectively. CYP2E1 activity was slightly induced, Km and Vmax were 170% of the control group. Bicyclol also mildly induces the phase Ⅱ enzymes UDPGT, GST and GR (the enzyme activities are 129%, 121% and 117% respectively of the control group). CONCLUSION: Bicyclol has some regulative effects on CYP450 and phase Ⅱ enzymes, and its potential impact on metabolic drug interactions deserves attention.