title: Nereistoxin and cartap neurotoxicity attributable to direct block of the insect nicotinic receptor/channel.
abstract: Nereistoxin (NTX) (4-dimethylamino-1,2-dithiolane) is the naturally occurring prototype for cartap [the bis(thiocarbamate) derivative of the NTX dithiol], which is generally regarded as a proinsecticide reverting to NTX. The aim of this study is to define the target site(s) for dithiolanes and dithiol esters. The affinity of [(3)H]NTX was not suitable for binding assays with honeybee (Apis mellifera) head membranes. However, NTX and cartap are equally potent, direct-acting, and competitive displacers of [(3)H]thienylcyclohexylpiperidine binding at the noncompetitive blocker (NCB) site of the Apis nicotinic acetylcholine receptor (nAChR)/channel. NTX also binds at the Apis [(3)H]imidacloprid agonist site, but cartap does not. As candidate metabolic pathways, sequential N-desmethylation and S-oxidation of NTX progressively reduce its potency at the NCB site and toxicity to houseflies. A P450 inhibitor reduces the toxicity of NTX and enhances it with cartap. Surprisingly, cartap is not just a pro-NTX but instead directly induces inhibitory neurotoxicity by blocking the nAChR/channel, whereas NTX may have dual NCB and agonist targets.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, USA.
authors.forename: Seog-Jong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D001516:Bees; D005260:Female; D006793:Houseflies; D007306:Insecticides / Q000494:pharmacology*; D008387:Marine Toxins / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D007306:Insecticides; D008387:Marine Toxins; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D013859:Thiocarbamates; C025633:nereistoxin; C032761:carbamothioic acid, S,S'-(2-(dimethylamino)-1,3-propanediyl) ester