In vitro assessment of susceptibility to toxic drug metabolites

有毒药物代谢物敏感性的体外评估

• 批准号: 62570309
• 负责人: NOMURA Fumio
• 金额: $ 1.22万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1987
• 资助国家: 日本
• 起止时间: 1987 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-62570309/
• 关键词: Drug-induced liver injury; peripheral blood mononuclear cells; Malotilate; hepatic microosmes; 末梢血単核球; 肝ミクロソ-ム; ハローセン; マロチレート; 薬物性肝障害; 肝ミクロソーム; アセトアミノフェン

We made an in vitro assessment of susceptibility to drug metabolites with malotilate as substrate. Peripheral-blood mononulcear cells(PBMCs) were incubated with malotilate(0.12mM) in the presence of the NADPH-generating system and hepatic microsomes(O.025mg protein/ml). Cytotoxicity of malotilate to PBMCs was assessed by trypan blue dye exclusion and LDH release to the culture media, being found to be enhanced by the addition of the NADPH-generating system. The result indicated a significant role of the metabolites in toxicity. More interestingly, the cytotoxicity was remarkably greater in patients with malotilate-induced liver injury than in controls. This in vitro system may be useful in predicting potential toxicity of drugs for selected patients.

我们以马洛替酸盐为底物进行了药物代谢物的体外药敏试验。外周血单核细胞(PBMC)在NADPH生成系统和肝微粒体(0.025 mg蛋白/ml)存在下与马洛替酸盐(0.12 mM)孵育。台盼蓝拒染法和乳酸脱氢酶释放法检测了马洛替酸盐对PBMC的细胞毒性，发现NADPH生成系统的加入可增强马洛替酸盐对PBMC的细胞毒性。结果表明，代谢产物在毒性中起着重要的作用。更有趣的是，在马洛替酸盐诱导的肝损伤患者中，细胞毒性显著高于对照组。这一体外系统可能有助于预测药物对选定患者的潜在毒性。

项目成果

Fumio Nomura et al.: "Clinical pharmacokinetics in patients with liver disease" IGAKUNO AYUMI 145:656-658, 1988.

Fumio Nomura 等：“肝病患者的临床药代动力学” IGAKUNO AYUMI 145：656-658，1988。

Fumio Nomura et al.: "Halothane hepatotoxicity and reductive metabolism of halothane in acute experimental liver injury in rats" Anesth.Analg. 67. 448-452 (1988)

Fumio Nomura 等人：“氟烷肝毒性和氟烷在大鼠急性实验性肝损伤中的还原代谢”Anesth.Analg。

野村文夫 他: "薬物活性化反応を利用した薬剤性肝障害in vitro診断の試み" 医学のあゆみ. 150. 565-566 (1989)

Fumio Nomura 等人：“尝试使用药物激活反应在体外诊断药物引起的肝损伤”，医学史 150. 565-566 (1989)。

Fumio Nomura et al.: "Detection of malotilate toxicity in vitro with peripheral blood mononuclear cells as targets- A preliminary study." Journal of Hepatology.

Fumio Nomura 等人：“以外周血单核细胞为目标的体外马洛替酯毒性检测 - 初步研究。”

Fumio Nomura et al.: "Halothane hepatotoxicity and reductive metabolism of halothane in acute experimental liver injury in rats" Anesth Analg.67. 448-452 (1988)

Fumio Nomura 等人：“氟烷肝毒性和氟烷在大鼠急性实验性肝损伤中的还原代谢”Anesth Analg.67。