A common naturally allyl isothiocyanates (AITC) from cruciferous vegetables in inhibiting CYP2B6 and CYP3A4 expression through a receptor-mediated activation

• Main Authors: Ching-Hao Cheng, 鄭慶浩
• Other Authors: Yun-Ping Lim
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/06066817744465833460

碩士 === 中國醫藥大學 === 藥學系碩士班 === 101 === Discrepancy expression and regulation of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in some drugs with narrow therapeutic index (TI). The most important DMEs including cytochrome P450 3A4 (CYP3A4) and CYP2B6. They are predominantly regulated by nuclear receptors (NR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Allyl isothiocyanate (AITC) is commonly found in cruciferous vegetables. It exhibits variety of biological functions, including antimicrobial and anticancer activity. However, the effect of AITC on the modulation of CYP450s is not well understood. In this study, we aimed to investigate the effect of AITC on the modulation of CYP450s through NRs. AITC inhibited the CYP3A4 enzyme activity, mRNA, protein expression and CYP2B6 protein expression. The results from CYP3A4 and CYP2B6 reporter activities showed that, AITC inhibits PXR- and CAR-mediated CYP3A4 and CYP2B6 promoter activities. Further mechanistic studies showed that AITC down regulated the expression of those CYP450s gene by disrupted the coregulation effects of PXR with steroid receptor cofactor-1 (SRC-1) and hepatocyte nuclear factor 4α (HNF4α). Our results indicated that modification of CYP450s by consumption of AITC could have important implications on drug safety.