Dataset Information

Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element.

ABSTRACT: Identifying agents that block tumor initiation is a goal of cancer prevention. The ability of a chemically varied group of agents to induce various drug metabolizing genes in livers of rats was examined. Sprague-Dawley rats were treated for 7 days with various agents in the diet or by gavage. The agents examined, which might be expected to respond via specific nuclear receptors (CAR, AhR) as well as antioxidant response elements (AREs), included Phase I/II inducers [5,6-benzoflavone (BF, 5000mg/kg diet), diallyl sulfide (DAS, 500mg/kg BW/day), ethoxyquin (EXO, 300mg/kg BW/day) and phenobarbital (PB, 500mg/kg diet)] or pure Phase II inducers [1,2-dithiol-3-thione (DTT, 500mg/kg diet), and cyclopentadithiolthione (CPDTT, 175mg/kg BW/day)]. Liver RNA expression was analyzed employing oligonucleotide microarrays. The agents yielded unique expression profiles. In genes with known AREs, the induction ratios (Levels Treated/Levels Controls) were: quinone oxidoreductase (BF, 8:1; DTT, 3.2:1; CPDTT, 3:1; DAS, 1.8:1; Exo, 1.7:1), glutatione transferase Pi (DTT, 36:1; CPDTT, 34:1; EXO, 8:1; DAS, 5:1; BF, 2.5:1), and aldehyde keto reductase 7A3 (AFAR) (DTT and CPDTT, 14:1; DAS, 6:1; EXO, 4:1; PB, 1.5:1). When the search included a wider variety of Phase II drug metabolizing enzymes, no clear pattern was observed. Agent induced gene expression and preventive activity in published carcinogen induced tumor models showed limited correlation; questioning whether measuring the induction of one or two genes (e.g., quinone reductase) is a surrogate for overall Phase II inducing (antioxidant) and potential anti-tumor activity.

SUBMITTER: Lubet RA

PROVIDER: S-EPMC3642098 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element.

Lubet Ronald A RA Yao Ruisheng R Grubbs Clinton J CJ You Ming M Wang Yian Y

Chemico-biological interactions 20090818 1

Identifying agents that block tumor initiation is a goal of cancer prevention. The ability of a chemically varied group of agents to induce various drug metabolizing genes in livers of rats was examined. Sprague-Dawley rats were treated for 7 days with various agents in the diet or by gavage. The agents examined, which might be expected to respond via specific nuclear receptors (CAR, AhR) as well as antioxidant response elements (AREs), included Phase I/II inducers [5,6-benzoflavone (BF, 5000mg/ ...[more]

PMID: 19695238

Similar Datasets

Project description: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-Dawley 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-MS/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-PD modeling was conducted based on Jusko's 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-?B, UGT1A1, or UGT1A6. Moderate increases (2-5-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK-PD 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-PD 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-PD studies of dietary cancer chemopreventive agents in human.

Dataset Information

Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element.

Publications

Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets