BREVETOXIN-6 (PBTX-6), A NONAROMATIC MARINE NEUROTOXIN, IS A LIGAND OF THE ARYL-HYDROCARBON RECEPTOR

Brevetoxins (PbTx) are a family of marine polyether toxins that exert their toxic action by activating voltage-sensitive sodium channels. Tw o forms of brevetoxin, PbTx-2 and -3, induce hepatic cytochrome P4501A 1, measured as ethoxyresorufin O-deethylase (EROD) activity, in redfis h and striped bass. P4501A1 induction is transcriptionally regulated t hrough the binding of a ligand, typically a planar aromatic compound, to the aryl hydrocarbon receptor (AhR) and subsequent complex formatio n with the dioxin response element (DRE), an upstream regulatory regio n of the CYP1A1 gene. To determine if PbTx, a nonaromatic compound, in duced EROD by this mechanism, two sets of experiments were performed. Initially, saturation binding assays with PbTx-2, -3, and -6 were carr ied out to determine if PbTx-2, -3, or -6 was an AhR ligand. Results s howed that PbTx-6 inhibited specific binding of dioxin to the AhR, whe reas PbTx-2 and -3 had no effect. Subsequently, gel retardation assays showed that PbTx-6 caused a concentration-dependent increase in AhR-D RE complex formation. The most abundant and neurotoxic forms of brevet oxin, PbTx-2 and -3, did not appear to be involved in this process. Ho wever, PbTx-6, the epoxide which is a likely biotransformation product , is at least one of the forms of PbTx involved in EROD induction. (C) 1997 Academic Press.