Mechanism for human-specific hepatotoxicity and development of prediction system

人类特异性肝毒性机制及预测系统开发

• 批准号: 17390039
• 负责人: YAMAZOE Yasushi
• 金额: $ 9.66万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390039/
• 关键词: flutamide; hepatotoxicity; Sult2a; lithocholic acid; CYP3A4; ampicillin; cholic acid; TCPOBOP; モデル動物; 毒性機序

To identify the mechanism for human-specific hepatotoxicity and develop the prediction system, flutamide and bile acid models were used. The metabolism of flutamide was analyzed using human CYP expressed microsomes. FLU-1-N-OH (N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine) which is a candidate of metabolic intermediate for flutamide-induced hepatotoxicity was produced from FLU-1 by human CYP3A4. In mice, FLU-1 N-hydroxylation was mainly catalyzed by Cyp isoforms different from Cyp3a isoforms. Furthermore, mouse hepatotoxicity model was established by co-treatment with FLU-1 and TCPOBOP. We are analyzing the mechanism for fulutamide-induced hepatotoxicity using the mouse model.To analyze the mechamism for hepatotoxicity through the interaction between endogenous compound (bile acid) and drug, C57/BL6 male mice were treated with cholic acid and ampicillin. Cholic acid (CA) or ampicillin treatment did not cause hepatotoxicity, but CA and ampicillin co-treatment cause severe hepatotoxicity in the mice. These results suggest the presence of the interaction between CA and ampicilin involved in hepatotoxicity. On the other hand, cholic acid treatment causes hepatotoxicity in fornesoid X receptor (FXR)-null mice. After co-treatment with 1.25% cholesterol (Chol), serum ALT and ALP activities were significantly decreased in FXR-null mice fed a 0.5% cholic acid diet, as compared to those of the CA diet controls. Clear decreases were observed on ileal bile acid absorption capacity estimated by a in situ loop method and contents of ileal Asbt protein in FXR-null mice fed the CA plus Chol diet. These results indicate a protective role of cholesterol against bile acid-induced toxicity and also suggest the presence of an FXR-independent suppressive mechanism of ileal bile acid absorption.

为了确定人类特异性肝毒性的机制并开发预测系统，使用了氟他胺和胆汁酸模型。利用人CYP表达的微粒体分析氟他胺的代谢。Flu-1-N-OH(N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine)是氟他胺肝毒性的候选代谢中间体。在小鼠中，Flu-1N-羟化主要由不同于CyP3A亚型的Cyp亚型催化。采用Flu-1和TCPOBOP联合处理的方法建立小鼠肝毒性模型。为了通过内源性化合物(胆汁酸)与药物的相互作用分析其肝毒性的机制，我们用胆酸和氨苄西林对C57/BL6雄性小鼠进行了治疗。胆酸(CA)或氨苄西林对小鼠无肝毒性，但CA与氨苄西林合用对小鼠有严重的肝毒性。这些结果提示，CA与氨基匹林之间存在相互作用，参与了肝毒性。另一方面，胆酸治疗引起福尔尼西德X受体(FXR)缺失小鼠的肝毒性。经1.25%胆固醇(Chol)共同处理后，饲喂0.5%胆酸饮食的FXR基因缺失小鼠的血清ALT和ALP活性较CA饮食对照组显著降低。用原位环法测定FXR基因缺失小鼠的回肠胆汁酸吸收能力和回肠Asbt蛋白含量均明显降低。这些结果表明，胆固醇对胆汁酸诱导的毒性具有保护作用，也表明回肠胆汁酸吸收存在FXR非依赖的抑制机制。

项目成果

Role for enhanced fecal excretion of bile acid in hydroxysteroid sulfotransferase-mediated protection against lithocholic acid-induced liver toxicity

增强胆汁酸粪便排泄在羟基类固醇磺基转移酶介导的针对石胆酸诱导的肝毒性的保护中的作用

• 发表时间: 2006
• 期刊: Xenobiotica 36
• 作者: M.Miyata;H.Watase;W.Hori;M.Shimada;K.Nagata;F.J.Gonzalez;Y.Yamazoe
• 通讯作者: Y.Yamazoe

Role for enhanced tecal excretion of bile acid in hydroxysteroid sulfotransferase-mediated protection against lithocholic acid-induced liver toxicity

增强胆汁酸的 tecal 排泄在羟基类固醇磺基转移酶介导的针对石胆酸诱导的肝毒性的保护中的作用

• 发表时间: 2006
• 期刊: Xenobiotica 36
• 作者: M.Miyata;H.Watase;W.Hori;M.Shimada;K.Nagata;F.J.Gonzalez;Y.Yamazoe
• 通讯作者: Y.Yamazoe

Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients

• DOI: 10.1124/dmd.105.008623
• 发表时间: 2006-05-01
• 期刊: DRUG METABOLISM AND DISPOSITION
• 影响因子: 3.9
• 作者: Goda, R;Nagai, D;Yamazoe, Y
• 通讯作者: Yamazoe, Y

Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase

• DOI: 10.2133/dmpk.21.315
• 发表时间: 2006-01-01
• 期刊: DRUG METABOLISM AND PHARMACOKINETICS
• 影响因子: 2.1
• 作者: Miyata, Masaaki;Matsuda, Yoshiki;Yamazoe, Yasushi
• 通讯作者: Yamazoe, Yasushi

Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyllhydroxylamine, in human liver microsomes and urine of prostate cancer patients

在人肝微粒体和前列腺癌患者尿液中检测氟他胺的新 N-氧化代谢物 N-[4-硝基-3-(三氟甲基)苯基羟胺

• 发表时间: 2006
• 期刊: Drug Metab.Dispos. (in press)
• 作者: M.Miyata;Y.Matsuda;H.Tsuchiya;H.Kitada;T.Akase;M.Shimada;K.Nagata;F.J.Gonzalez;Y.Yamazoe;R.Goda
• 通讯作者: R.Goda