Effects of α-glucosidase inhibitors on cytochrome P450

α-葡萄糖苷酶抑制剂对细胞色素P450的影响

基本信息

批准号：
10670344
负责人：
WANG Peiyu
金额：
$ 1.47万
依托单位：
Yamanashi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

We studied the effects of α-glucosidase inhibitors (acarbose and voglivose) on cytochrome P450 (CYP) and hepatotoxicity Of carbon tetrachloride (CClィイD24ィエD2) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with CYP2E1. We began the study with acarbose. Male Sprague-Dawley rots were kept on a daily ration (20 g) of powdered chow diet containing 0, 20, 40 or 80 mg/100 g of acarbose, with drinking water containing 0 or 10% of ethanol (v/v). Three weeks later, the rats were either killed for an in vitro metabolism study or challenged with 0.50 g/kg CCl ィイD24ィエD2 po or 0.75 g/kg AP ip. The ethanol increased the hepatic microsomal CYP2E1 level and the rate of dimethylnitosamine (DMN) demethylation. The 40 or 80 mg/100 g acarbose diet, which alone increased the CYP2E1 level and the rate of DMN demethylation, augmented the enzyme induction by ethanol. The 40 or 80 mg/100 g acarbose diet alone potentiated CClィイD24ィエD2 and AP hepatotoxicity, as evidenced by significantly increased levels of both ALT and AST in the plasma of rots pretreated with acarbose. Ethanol alone also potentiated the toxicity of both chemicals. When the 40 or 80 mg/100 g acarbose diet was combined with ethanol, the ethanol-induced potential/on of CCィイD24ィエD2 and AP hepatotoxicity was augmented. We performed the similar experiment on voglivose and found it (5.0 or 10.0 mg/100 g diet, 3 weeks) induced CYP2E1 and increased hepatotoxicity of CCィイD24ィエD2 (0.50 g/kg). Our study demonstrated that high doses of α-glucosidase inhibitors can potentiate CClィイD24ィエD2 and AP hepatotoxicity in rats by inducing hepatic CYP2E1.

我们研究了 α-葡萄糖苷酶抑制剂（阿卡波糖和伏格列波糖）对大鼠细胞色素 P450 (CYP) 的影响以及四氯化碳 (CCD24D2) 和对乙酰氨基酚 (AP) 的肝毒性，这两种药物均通过与 CYP2E1 相关的生物激活发挥毒性作用。研究开始时，雄性斯普拉格-道利腐烂每天饲养一次。日粮（20克）含有0、20、40或80毫克/100克阿卡波糖的粉末饲料，以及含有0或10%乙醇（v/v）的饮用水。三周后，处死大鼠。体外代谢研究或用 0.50 g/kg CCl d24 po 或 0.75 g/kg AP ip 进行攻击，乙醇增加了肝微粒体 CYP2E1 水平和二甲基亚硝胺 (DMN) 去甲基化率 40 或 80 mg/100 g 阿卡波糖饮食单独增加了 CYP2E1 水平和 DMN 去甲基化率，40 或 80 mg 乙醇增强了酶诱导。 /100 g 单独的阿卡波糖饮食可增强 CCl D24 和 AP 肝毒性，如单独用阿卡波糖预处理的腐烂动物血浆中 ALT 和 AST 的水平显着增加，这表明当 40 或 80 mg/100 g 阿卡波糖饮食与乙醇结合时，乙醇诱导的潜力也增强。 CCIID24IED2 和 AP 肝毒性增强。我们对伏格列波糖进行了类似的实验，发现它（5.0 或）。 10.0 mg/100 g 饮食，3 周）诱导 CYP2E1 并增加 CClD24D2（0.50 g/kg）的肝毒性。我们的研究表明，高剂量的 α-葡萄糖苷酶抑制剂可以通过诱导肝脏 CYP2E1 来增强 CClD24D2 和 AP 的肝毒性。