TY - JOUR
T1 - Induced expression of drug metabolizing enzymes by preventive agents
T2 - Role of the antioxidant response element
AU - Lubet, Ronald A.
AU - Yao, Ruisheng
AU - Grubbs, Clinton J.
AU - You, Ming
AU - Wang, Yian
N1 - Funding Information:
The authors would like to thank Ms. Mary Jo Cagle and Jeanne Hale for their editorial assistance in the preparation of this manuscript. The funding for the studies was provided in part by NCI Contract Number HHSN261200433001C .
PY - 2009/11/10
Y1 - 2009/11/10
N2 - 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, 5000 mg/kg diet), diallyl sulfide (DAS, 500 mg/kg BW/day), ethoxyquin (EXO, 300 mg/kg BW/day) and phenobarbital (PB, 500 mg/kg diet)] or pure Phase II inducers [1,2-dithiol-3-thione (DTT, 500 mg/kg diet), and cyclopentadithiolthione (CPDTT, 175 mg/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.
AB - 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, 5000 mg/kg diet), diallyl sulfide (DAS, 500 mg/kg BW/day), ethoxyquin (EXO, 300 mg/kg BW/day) and phenobarbital (PB, 500 mg/kg diet)] or pure Phase II inducers [1,2-dithiol-3-thione (DTT, 500 mg/kg diet), and cyclopentadithiolthione (CPDTT, 175 mg/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.
KW - Antioxidant response element
KW - Chemopreventive agents
KW - Phase I/II inducers
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U2 - 10.1016/j.cbi.2009.08.011
DO - 10.1016/j.cbi.2009.08.011
M3 - Article
C2 - 19695238
AN - SCOPUS:70349627876
SN - 0009-2797
VL - 182
SP - 22
EP - 28
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1
ER -