title: Brevetoxin-6 (PbTx-6), a nonaromatic marine neurotoxin, is a ligand of the aryl hydrocarbon receptor.
abstract: Brevetoxins (PbTx) are a family of marine polyether toxins that exert their toxic action by activating voltage-sensitive sodium channels. Two forms of brevetoxin, PbTx-2 and -3, induce hepatic cytochrome P4501A1, measured as ethoxyresorufin O-deethylase (EROD) activity, in redfish and striped bass. P4501A1 induction is transcriptionally regulated through the binding of a ligand, typically a planar aromatic compound, to the aryl hydrocarbon receptor (AhR) and subsequent complex formation with the dioxin response element (DRE), an upstream regulatory region of the CYP1A1 gene. To determine if PbTx, a nonaromatic compound, induced EROD by this mechanism, two sets of experiments were performed. Initially, saturation binding assays with PbTx-2, -3, and -6 were carried out to determine if PbTx-2, -3, or -6 was an AhR ligand. Results showed that PbTx-6 inhibited specific binding of dioxin to the AhR, whereas PbTx-2 and -3 had no effect. Subsequently, gel retardation assays showed that PbTx-6 caused a concentration-dependent increase in AhR-DRE complex formation. The most abundant and neurotoxic forms of brevetoxin, PbTx-2 and -3, did not appear to be involved in this process. However, PbTx-6, the epoxide which is a likely biotransformation product, is at least one of the forms of PbTx involved in EROD induction.
authors.affiliation: Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis 95616, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Washburn
authors.forename: K S
authors.initials: KS
authors.lastname: Rein
authors.forename: D G
authors.initials: DG
authors.lastname: Baden
authors.forename: P J
authors.initials: PJ
authors.lastname: Walsh
authors.forename: D E
authors.initials: DE
authors.lastname: Hinton
authors.forename: K
authors.initials: K
authors.lastname: Tullis
authors.forename: M S
authors.initials: MS
authors.lastname: Denison
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002499:Centrifugation, Density Gradient; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006168:Guinea Pigs; D008099:Liver / Q000378:metabolism*; D008297:Male; D008387:Marine Toxins / Q000378:metabolism* / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D035964:Oxocins; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D019324:beta-Naphthoflavone / Q000494:pharmacology; D000095702:Polyether Toxins
chemical_list: D019363:Cytochrome P-450 CYP1A1; D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019324:beta-Naphthoflavone; C053342:brevetoxin; D000095702:Polyether Toxins