异烟肼长期治疗导致小鼠肝脏中原卟啉IX蓄积。
Chronic Treatment with Isoniazid Causes Protoporphyrin IX Accumulation in Mouse Liver.
作者信息
Sachar Madhav, Li Feng, Liu Ke, Wang Pengcheng, Lu Jie, Ma Xiaochao
机构信息
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
Department of Molecular and Cellular Biology, Baylor College of Medicine , Houston, Texas 77030, United States.
出版信息
Chem Res Toxicol. 2016 Aug 15;29(8):1293-7. doi: 10.1021/acs.chemrestox.6b00121. Epub 2016 Aug 2.
Abstract
Isoniazid (INH) can cause hepatotoxicity. In addition, INH is contraindicated in patients suffering from porphyrias. Our metabolomic analysis revealed that chronic treatment with INH in mice causes a hepatic accumulation of protoporphyrin IX (PPIX). PPIX is an intermediate in the heme biosynthesis pathway, and it is also known as a hepatotoxin. We further found that INH induces delta-aminolevulinate synthase 1 (ALAS1), the rate-limiting enzyme in heme biosynthesis. We also found that INH downregulates ferrochelatase (FECH), the enzyme that converts PPIX to heme. In summary, this study illustrated that chronic treatment with INH causes PPIX accumulation in mouse liver in part through ALAS1 induction and FECH downregulation. This study also highlights that drugs can disrupt the metabolic pathways of endobiotics and increase the risk of liver damage.
摘要
异烟肼（INH）可导致肝毒性。此外，患有卟啉症的患者禁用INH。我们的代谢组学分析表明，小鼠长期接受INH治疗会导致肝脏中原卟啉IX（PPIX）蓄积。PPIX是血红素生物合成途径中的一种中间体，也是一种肝毒素。我们进一步发现，INH可诱导血红素生物合成中的限速酶δ-氨基乙酰丙酸合酶1（ALAS1）。我们还发现，INH可下调将PPIX转化为血红素的酶——亚铁螯合酶（FECH）。总之，本研究表明，长期使用INH治疗会部分通过诱导ALAS1和下调FECH导致小鼠肝脏中PPIX蓄积。本研究还强调，药物可扰乱内源性物质的代谢途径并增加肝损伤风险。
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