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KMID : 1142220160110010001
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Regulatory Research on Food, Drug & Cosmetic
2016 Volume.11 No. 1 p.1 ~ p.8
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Comparative Research of Cytochrome P450 In vitro Induction by Bosentan in Human Hepatocytes
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Bae Young-Ji
An Sun-Young
Yun Jae-Suk
Cha Hye-Jin
Sin Ji-Soon
Kim Young-Hoon
Kim Hyung-Soo
Park Hye-Kyung
Han Kyoung-Moon
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Abstract
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Human liver cytochrome P450 (CYP450) isozymes are principle drug-metabolizing enzymes. The US FDA and EU EMA guidelines suggest that along with enzyme activity measurements, mRNA expression levels could be used to evaluate CYP450 enzyme induction. We evaluated the potential induction ability of Bosentan, as a pulmonary arterial hypertension drug, on CYP450 isozymes (CYP1A2, 2B6 and 3A4) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and quantitative real-time polymerase chain reaction (qRT-PCR). Bosentan treatment increased CYP3A4 mRNA expression in HMC478, HMC923 cell, and it were at least 10 times higher than enzyme activity of that. CYP2B6 mRNA expression was induced in HMC478. CYP450 metabolism was established In vitro by determining enzymatic activity using LC-MS/MS which involves a complex method and utilizes expensive equipment. However, qRT-PCR is a simple and sensitive method for monitoring changes in mRNA expression. Therefore, we thought that mRNA expression measurement is a useful tool for detection of CYP450 isozymes induction.
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KEYWORD
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CYP450, mRNA expression, enzyme activity, LC-MS/MS, Bosentan
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