十字花科中常見之天然物烯丙基異硫氰酸酯(AITC)由抑制受體活化CYP2B6及CYP3A4表現之探討

鄭慶浩

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十字花科中常見之天然物烯丙基異硫氰酸酯(AITC)由抑制受體活化CYP2B6及CYP3A4表現之探討

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

鄭慶浩 , Masters　　Advisor：林雲冰　　

繁體中文

細胞色素P450 ；異硫氰酸；藥物交互作用； CYP3A4 ； CYP2B6 ； Drug drug interaction ； Cytochrome P450 ； AITC ； Allyl isothiocyanate ； PXR ； CAR ； CYP3A4 ； CYP2B6

Abstract │ Reference (68) │ Altmetrics

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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.

Reference ( 68 ) 〈TOP〉

Baes, M., Gulick, T., Choi, H. S., Martinoli, M. G., Simha, D. and Moore, D. D. (1994). "A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements." Mol Cell Biol 14(3): 1544-1552.
連結：
Blumberg, B. and Evans, R. M. (1998). "Orphan nuclear receptors--new ligands and new possibilities." Genes Dev 12(20): 3149-3155.
連結：
Bollard, M., Stribbling, S., Mitchell, S. and Caldwell, J. (1997). "The disposition of allyl isothiocyanate in the rat and mouse." Food Chem Toxicol 35(10-11): 933-943.
連結：
Bombail, V., Taylor, K., Gibson, G. G. and Plant, N. (2004). "Role of Sp1, C/EBP alpha, HNF3, and PXR in the basal- and xenobiotic-mediated regulation of the CYP3A4 gene." Drug Metab Dispos 32(5): 525-535.
連結：
Caraco, Y. (1998). "Genetic determinants of drug responsiveness and drug interactions." Ther Drug Monit 20(5): 517-524.
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