目的 发现不同剂量海藻-昆布药对提取物对大鼠肝微粒体代谢酶的诱导或抑制作用, 预测服用海藻-昆布药对时可能出现的药物-药物相互作用及肝脏毒性。方法 雌雄各半SD大鼠18只, 被随机分为海藻-昆布药对低、高剂量组和对照组, 低、高剂量组大鼠分别ig给予海藻-昆布药对提取物10.8、86.4 g/(kg·d), 连续经口给药15 d后麻醉处死, 取肝组织制备肝微粒体及HE染色石蜡切片。通过肝微粒体体外孵育方法测定3种肝脏CYP450同工酶特异性底物非那西丁(CYP1A2)、氯唑沙宗(CYP2E1)及咪达唑仑(CYP3A4)的降解和代谢产物生成量来评价肝药酶的诱导或抑制作用, 并以光镜下的组织病理切片检查来考察其肝毒性。结果 低剂量组大鼠无显著诱导或抑制3种CYP450代谢酶亚型1A2、2E1和3A4现象, 肝组织出现了肝窦扩张、轻度水肿等适应性改变, 高剂量组能显著诱导CYP3A4亚型, 但也不能显著的诱导或抑制肝微粒体代谢酶CYP1A2、CYP2E1亚型, 肝组织出现了脂肪变、点状坏死等可逆性损伤。结论 海藻-昆布药对具有诱导肝微粒体代谢酶CYP3A4的作用和轻微的肝细胞毒性, 高剂量经口给药能引起有临床意义的CYP450酶的诱导现象和肝脏损伤并可能导致不期望的药物-药物相互作用。
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.