Abstract
Sanguinarine's use in human clinical applications is currently controversial. While some studies have demonstrated sanguinarine's anti-inflammatory and anti-oxidant properties, other investigations reported sanguinarine's procarcinogenic effects. Like the tobacco-associated carcinogen, benzo(a)pyrene (B(a)P), sanguinarine is a polycyclic aromatic hydrocarbon (PAH). PAH exposure activates the aryl hydrocarbon transcription activating factor (AhR), resulting in nuclear translocation, binding to the aryl hydrocarbon nuclear translocator (ARNT), which thereby increases expression of a pool of carcinogen metabolizing enzymes. The goal of this study was to investigate whether sanguinarine activates this PAH-associated signaling cascade in human oral cells and tissues. Our results demonstrate that sanguinarine: (i) results in formation of the AhR-ARNT complex, (ii) induces AhR-associated gene expression, (iii) inhibits cytochrome P450 1A1 (CYP 1A1) microsomal oxidative activity and (iv) pretreatment upregulates CYP 1A1 function. Collectively, these data provide evidence that sanguinarine activates PAH-associated signaling and metabolic pathways. Notably, previous studies have demonstrated that mammalian hepatic microsomes metabolize sanguinarine to a mutagenic epoxide. Persons who respond to sanguinarine exposure with induction of primarily Phase I relative to Phase II enzymes are, therefore, at risk for sanguinarine bioactivation and its potential mutagenic effects.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Alkaloids / toxicity*
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
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Aryl Hydrocarbon Hydroxylases / biosynthesis*
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Receptor Nuclear Translocator
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Benzo(a)pyrene / metabolism
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Benzophenanthridines
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Carcinogens / metabolism
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Cell Line, Tumor
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Cytochrome P-450 CYP1A1 / antagonists & inhibitors
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Cytochrome P-450 CYP1A1 / biosynthesis
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Cytochrome P-450 CYP1A1 / genetics
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Cytochrome P-450 CYP1B1
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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Dose-Response Relationship, Drug
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Enzyme Induction / drug effects
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Humans
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Isoquinolines
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Keratinocytes / drug effects
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Keratinocytes / enzymology*
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Keratinocytes / pathology
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Male
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Middle Aged
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Mouth Mucosa / drug effects
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Mouth Mucosa / enzymology*
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Mouth Mucosa / pathology
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Mouthwashes / toxicity*
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Phenanthridines / toxicity*
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Receptors, Aryl Hydrocarbon / biosynthesis*
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Receptors, Aryl Hydrocarbon / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Up-Regulation / drug effects
Substances
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ARNT protein, human
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Alkaloids
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Benzophenanthridines
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Carcinogens
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DNA-Binding Proteins
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Isoquinolines
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Mouthwashes
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Phenanthridines
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Receptors, Aryl Hydrocarbon
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Transcription Factors
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Aryl Hydrocarbon Receptor Nuclear Translocator
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Benzo(a)pyrene
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sanguinarine
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Aryl Hydrocarbon Hydroxylases
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CYP1B1 protein, human
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1B1