Identification of genes involved in drug-induced hepatotoxicity

点击翻译按钮获取中文摘要

In this study, we investigated the genes involved in drug-induced hepatotoxicity. The drugs we focused in this study were acetaminophen, isoniazid, metformin and buformin. To identify the genes changes their expression by the drugs in human hepatic HepG2 cells, a subtractive cDNA library was constructed. Through differential screening of the library, several clones were identified as drug induced or reduced gene. For example, acetaminophen and isoniazid increased lysyl hydroxylase, 2 (LH2) expression, and acetaminophen decreased thymidine synthetase expression. Metformin and buformin decreased glyceraldehyde 3-phosphate dehydrogenase expression and increased beta actin expression.Lysyl hydroxylase catalyzes the posttranslational hydroxylation of lysine residues in collagen. Hydroxylation of lysine residues in collagen molecules is essential for the formation and stabilization of collagen crosslinks, and is believed to act as an important role in the process of hepatic fibrosis. We therefore focused in the increased LH2 expression by the drugs. To examine the mechanism of LH2 expression increased by the drugs, we prepared the reporter plasmid containing the LH2 upstream region, and found that the increased mRNA expression was due to the transcriptional activation of LH2 by the drugs. In addition, we found that the two drugs induce the expression of transcriptional factor c-myb and the overexpression of c-myb induces LH2 mRNA expression and the transcriptional activation of LH2. From these results, increased LH2 expression may involve in the hepatotoxicity by acetaminophen and isoniazid.