藥物代謝酵素不一致的表現或被誘導、抑制之下，可能會造成治療指數(therapeutic index)狹窄藥物的藥物不良反應。Cytochrome P450 3A4 (CYP3A4)為肝臟中重要的代謝酵素，主要為核內接受體類酯醇X受體(pregnane X receptor (PXR))所調控。芝麻素(sesamin)為芝麻中木脂素 (lignan) 類化合物的主要成分，並且有許多生物活性功能。但是，芝麻素對於CYP3A4的調控仍然不清楚。在此次研究當中，以PXR-mediated CYP3A4 啟動區活性、CYP3A4活性、mRNA表現量以及蛋白質表現量探討可能的機轉。結果顯示，sesamin藉由抑制PXR的活性而減少其他藥物對CYP3A4的誘導量，並且有劑量依存性。更進一步的機轉研究顯示sesamin抑制PXR的活性是因為降低PXR與steroid receptor cofactor-1 和hepatocyte nuclear factor 4α之間的交互作用。本篇研究結果顯示，sesamin為PXR抑制劑，因此，sesamin可能藉由抑制CYP3A4代謝酵素而使原本由CYP3A4所代謝的藥物血中濃度改變，進而造成臨床上的藥物交互作用。
Induction or reduction of drug-metabolizing enzymes is probably the most common cause of clinical drug interactions and adverse drug reaction. The most important enzyme in the liver for drug metabolism is cytochrome P450 3A4 (CYP3A4), which contributes to the metabolism of approximately 60% the drugs. Pregnane X receptor (PXR) is a nuclear receptor and a major transcriptional factor for CYP3A4. Sesamin is the major lignan in sesame seeds, and has many biological activities. However, effect of sesamin on the modulation of CYP3A4 is not well understood. In this study, we aimed to investigate the mechanism of the effect of sesamin on CYP3A4 by PXR-mediated CYP3A4 promoter activity, CYP3A4 activity, mRNA expression, and protein expression. Results showed that sesamin decreased CYP3A4 expression by inhibiting PXR activity. Furthermore, we found that sesamin inhibited PXR activity via disrupting the interaction between PXR and steroid receptor cofactor-1 and hepatocyte nuclear factor 4α.In our study, the results showed that sesamin is a novel PXR inhibitor. Therefore, sesamin might arouse drug interaction through inhibition of CYP3A4.
