藥物不良反應常見的原因為個體調控藥物代謝?(drug-metabolizing enzymes, DMEs) 的表現差異不同，因此使用治療指數 (therapeutic index, TI) 狹窄的藥品後容易造成不良反應。其中位於肝臟重要的代謝?，細胞色素P450 3A4 (Cytochrome P450 3A4, CYP3A4) 和細胞色素P450 2B6 (Cytochrome P450 2B6, CYP2B6) 主要受細胞核接受體 (nuclear receptors, NR)，類酯醇X受體 (pregnane X receptor, PXR) 和構雄甾烷受體 (constitutive androstane receptor, CAR) 調控。烯丙基異硫氰酸酯 (Allyl isothiocyanates, AITC） 普遍存在於十字花科 (cruciferous) 蔬菜，AITC有許多生物功能，包括抗菌和抗癌活性，但目前對於CYP450的調控仍不清楚。在本研究中，我們的目的是探討AITC是否藉由細胞核接受體來影響CYP450。AITC抑制了細胞色素P450 3A4酵素活性、mRNA、蛋白表現並且抑制細胞色素P450 2B6蛋白表現。也由CYP3A4及CYP2B6的報導基因分析，AITC會抑制PXR及CAR的活化。進一步也發現AITC藉由破壞共同活化因子類固醇受體輔助因子1 (steroid receptor cofactor-1, SRC-1) 和肝細胞核因子4 (hepatocyte nuclear factor 4α, HNF4α)與PXR的交互作用，來達到抑制CYP3A4啟動子的表現。我們的研究結果是AITC對於影響CYP450s的活性表現，在用藥安全上具有重要的意義。
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.
