目的 發(fā)現(xiàn)不同劑量海藻-昆布藥對(duì)提取物對(duì)大鼠肝微粒體代謝酶的誘導(dǎo)或抑制作用, 預(yù)測(cè)服用海藻-昆布藥對(duì)時(shí)可能出現(xiàn)的藥物-藥物相互作用及肝臟毒性。方法 雌雄各半SD大鼠18只, 被隨機(jī)分為海藻-昆布藥對(duì)低、高劑量組和對(duì)照組, 低、高劑量組大鼠分別ig給予海藻-昆布藥對(duì)提取物10.8、86.4 g/(kg·d), 連續(xù)經(jīng)口給藥15 d后麻醉處死, 取肝組織制備肝微粒體及HE染色石蠟切片。通過(guò)肝微粒體體外孵育方法測(cè)定3種肝臟CYP450同工酶特異性底物非那西丁(CYP1A2)、氯唑沙宗(CYP2E1)及咪達(dá)唑侖(CYP3A4)的降解和代謝產(chǎn)物生成量來(lái)評(píng)價(jià)肝藥酶的誘導(dǎo)或抑制作用, 并以光鏡下的組織病理切片檢查來(lái)考察其肝毒性。結(jié)果 低劑量組大鼠無(wú)顯著誘導(dǎo)或抑制3種CYP450代謝酶亞型1A2、2E1和3A4現(xiàn)象, 肝組織出現(xiàn)了肝竇擴(kuò)張、輕度水腫等適應(yīng)性改變, 高劑量組能顯著誘導(dǎo)CYP3A4亞型, 但也不能顯著的誘導(dǎo)或抑制肝微粒體代謝酶CYP1A2、CYP2E1亞型, 肝組織出現(xiàn)了脂肪變、點(diǎn)狀壞死等可逆性損傷。結(jié)論 海藻-昆布藥對(duì)具有誘導(dǎo)肝微粒體代謝酶CYP3A4的作用和輕微的肝細(xì)胞毒性, 高劑量經(jīng)口給藥能引起有臨床意義的CYP450酶的誘導(dǎo)現(xiàn)象和肝臟損傷并可能導(dǎo)致不期望的藥物-藥物相互作用。

Objective To investigate the inhibitory or inducing effects on cytochromeP450(CYP) and study the hepatotoxicity of Chinese medicine pair (CMP) of Sargassum fusiforme-Laminaria japonica. Methods Eighteen SD rats, half male and half female, were randomly divided into three groups: low-dose, high-dose, and control groups. All groups were treated with crude polysaccharides extracted from S. fusiforme-L. japonica or saline by ig administration for 2 weeks. All liver microsomes were prepared by the calcium-ion deposition method. Three specific probe drugs were utilized for co-incubating in rat liver microsomes, including phenacetin (1A2), chlorzoxazone (2E1), and midazolam (3A4). The concentration of the metabolites formed from each substrate was determined by HPLC. Pathomorphology of rat liver was observed with HE staining to describe the potential hepatotoxicity. Results The CMP with low dose (10.8 g/kg/d) had no significant inhibitory or inducing effects on liver microsome CYP450 while some adaptive changes occurred in the rat liver (e.g. cellular swelling and dilation of hepatic sinusoid). The high dose one (86.4 g/kg/d) had a significant inducing effect on CYP3A4 but no effect on CYP1A2 or CYP2E1 while some irreversibly damages happened in the liver (e.g. fatty change and point necrosis). Conclusion As for clinic applying, the drug-drug interactions as well as hepatic injury might occur when the CMP of S. fusiforme-L. japonica taken in high dose administration.

上海市科委重點(diǎn)實(shí)驗(yàn)室課題(13DZ2272500)