Pharmacokinetics and Pharmacodynamics of Phase II Drug Metabolizing/Antioxidant Enzymes Gene Response by Anticancer Agent Sulforaphane in Rat Lymphocytes
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- 作者：Hu Wang ; Tin Oo Khor ; Qian Yang ; Ying Huang ; Tien-yuan Wu ; Constance Lay-Lay Saw ; Wen Lin ; Ioannis P. Androulakis ; Ah-Ng Tony Kong
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：October 1, 2012
- 年：2012
- 卷：9
- 期：10
- 页码：2819-2827
- 全文大小：318K
- 年卷期：v.9,no.10(October 1, 2012)
- ISSN：1543-8392
文摘
This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of phase II drug metabolizing enzymes (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (iv) administration of an anticancer phytochemical sulforaphane (SFN). SFN was administered intravenously to four groups of male Sprague鈥揇awley JVC rats each group comprising four animals. Blood samples were drawn at selected time points. Plasma were obtained from half of each of the blood samples and analyzed using a validated LC鈥揗S/MS method. Lymphocytes were collected from the remaining blood samples using Ficoll-Paque Plus centrifuge medium. Lymphocyte RNAs were extracted and converted to cDNA, quantitative real-time PCR analyses were performed, and fold changes were calculated against those at time zero for the relative expression of Nrf2-target genes of phase II DME/antioxidant enzymes. PK鈥揚D modeling was conducted based on Jusko鈥檚 indirect response model (IDR) using GastroPlus and bootstrap method. SFN plasma concentration declined biexponentially and the pharmacokinetic parameters were generated. Rat lymphocyte mRNA expression levels showed no change for GSTM1, SOD, NF-魏B, UGT1A1, or UGT1A6. Moderate increases (2鈥?-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK鈥揚D analyses using GastroPlus and the bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. Our present study shows that SFN could induce Nrf2-mediated phase II DME/antioxidant mRNA expression for NQO1, GSTT1, Nrf2, GPx, Maf, and HO-1 in rat lymphocytes after iv administration, suggesting that Nrf2-mediated mRNA expression in lymphocytes may serve as surrogate biomarkers. The PK鈥揚D IDR model simultaneously linking the plasma concentrations of SFN and the PD response of lymphocyte mRNA expression is valuable for quantitating Nrf2-mediated effects of SFN. This study may provide a conceptual framework for future clinical PK鈥揚D studies of dietary cancer chemopreventive agents in human.