Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element.
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.
Lubet
Ronald A
RA
Division of Cancer Prevention, National Cancer Institute, Executive Plaza North, Suite 2110, 6130 Executive Boulevard, Bethesda, MD 20852, USA. lubetr@mail.nih.gov
Yao
Ruisheng
R
Grubbs
Clinton J
CJ
You
Ming
M
Wang
Yian
Y
D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects*; D005015:Ethoxyquin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000494:pharmacology
C522589:5,6-dihydrocyclopenta-1,2-dithiole-3-thione; D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D013440:Sulfides; D013871:Thiones; D013876:Thiophenes; D019324:beta-Naphthoflavone; C038491:allyl sulfide; D005015:Ethoxyquin; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; C049325:1,2-dithiol-3-thione; D010634:Phenobarbital
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