title: Endothall thioanhydride: structural aspects of unusually high mouse toxicity and specific binding site in liver.
abstract: The thioanhydride of the herbicide endothall is highly toxic to mice on intraperitoneal (ip) administration, with an LD50 of 0.31 mg/kg compared to 4.0 and 14 mg/kg for the corresponding anhydride and dicarboxylic acid, respectively. This unusually high toxicity of the thioanhydride relative to the anhydride and dicarboxylic acid is observed also for the 5,6-dehydro analogue and less so for the 2-methyl and 5-endo-(cyanomethyl) analogues but not for five related series of 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acids, anhydrides, and thioanhydrides with various 2-, 3-, 5- and 6-substituents. Synthesis of [exo,exo-5,6-3H]endothall thioanhydride ([3H]ETA) allowed radioligand binding studies with mouse liver cytosol, which was found to have a high-affinity binding site (apparent dissociation constant 32 nM, maximum number of binding sites 2.8 pmol/mg of protein, greater than 95% specific binding). The potency of 18 endothall analogues as dicarboxylic acids and anhydrides for inhibiting [3H]ETA binding in vitro is a very good predictor of their mouse toxicity (r = 0.95, n = 16; two related compounds are of low activity in both assays) in a similar manner to earlier studies with [3H]-2,3-dimethylendothall anhydride (cantharidin) (r = 0.83, n = 15). This correlation does not extend to most of the thioanhydrides, particularly the 2,3-dimethyl and 2,3-trimethylene compounds, which are the most stable to hydrolytic cleavage. The [3H]ETA binding site of liver cytosol is inhibited 75-80% by LD50 doses of 2,3-dimethylendothall anhydride and thioanhydride but only 24% by an LD50 dose of endothall thioanhydride, with assays 30 min after ip treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Department of Entomological Sciences, University of California, Berkeley 94720.
authors: N
authors: N
authors: Kawamura
authors: Y M
authors: YM
authors: Li
authors: J L
authors: JL
authors: Engel
authors: W G
authors: WG
authors: Dauben
authors: J E
authors: JE
authors: Casida
mesh_terms: D000812:Anhydrides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D002193:Cantharidin / Q000633:toxicity; D003998:Dicarboxylic Acids / Q000378:metabolism / Q000633:toxicity*; D006868:Hydrolysis; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000812:Anhydrides; D003998:Dicarboxylic Acids; C100030:endothall; D002193:Cantharidin