Partition distribution of insecticides as a critical factor affecting their rates of absorption from water and relative toxicities to fish

Loaches, Misgurnus anguillicaudatus (Cantor), a common fish in Taiwan, were treated with DDT, dieldrin, and monocrotophos by continuous exposure in aqueous solutions (or suspensions) and by injection. DDT and dieldrin were 150 and 220 times more toxic, respectively, than monocrotophos, to the fish exposed in aqueous solutions (24-hr LC50), but only 1/9 and 1/4 as toxic as monocrotophos by injection (24-hr LD50). Results of GLC analyses indicate that, at the end of 24-hr exposure, 96.5% of DDT, 92.7% of dieldrin, and 14.3% of monocrotophos were absorbed by loaches from aqueous solutions. The initial rates of absorption for DDT and dieldrin were about 10 to 20 times faster than that for monocrotophos. The large differences in relative toxicity may be due to partition distribution which in turn caused differences in absorption, as DDT and dieldrin are lipophilic and monocrotophos is hydrophilic. Statistical analysis of the relationship between fish toxicities and partition coefficients supports the present finding. The coefficient of correlation is 0.70 between parition coefficients (benzene/water) and toxicities to fish (rainbow trout) of 12 organophosphorus insecticides, 0.74 between coefficients and corrected fish toxicities, and 0.96 between partition coefficients and corrected fish toxicities for organophosphates only. Results of analyses are significant at less than 1% probability level. Similar correlation was also obtained between partition coefficients for hexane/water and toxicities of 8 organophosphorus and 5 organochlorine insecticides to rainbow trout.     

The expression, origin and function of tenascin during peripheral nerve formation in the chick

During development of the peripheral nervous system, the extracellular matrix molecule tenascin has been found to be closely associated with growing axons. However, its origin and function in peripheral nerve formation are far from clear. In this study, we examined the expression of tenascin during outgrowth of sensory, motor and sympathetic preganglionic axons, and assessed its origin and function in peripheral nerve formation. During outgrowth of sensory and motor axons, a high concentration of tenascin and its mRNA was found to surround sensory and motor axons in the newly formed spinal nerves. The source of this tenascin was examined through a series of surgical manipulations. Neural crest removals did not alter the distribution of tenascin protein or its mRNA surrounding the spinal nerves. Transplantation of quail somites into chick embryos showed that, similar to the distribution of tenascin, there is a high concentration of somitic cells surrounding the spinal nerves. Moreover, somite removals resulted in a reduction of the tenascin and tenascin mRNA surrounding the spinal nerves. Taken together, these results suggest that the majority of the tenascin surrounding the spinal nerves is of somitic origin. Possible functions of tenascin associated with peripheral nerve formation were examined through injections of tenascin or its antiserum into individual somites prior to or during axon outgrowth. Injections of tenascin or its antiserum did not alter the trajectory of peripheral axons in the anterior half of the somite, nor produce gross abnormalities in the morphology of peripheral nerves, suggesting that tenascin does not play a crucial role in the early formation of peripheral nerves.     

Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease

We report highly potent, selective, and low cost bifunctional acetylcholinesterase (AChE) inhibitors developed by our two-step prototype optimization strategy utilizing computer modeling of ligand docking with target proteins: 1) identify low affinity sites normally missed by x-ray crystallography; and 2) design bifunctional analogs capable of simultaneous binding at the computer-determined low affinity site and the x-ray-identified high affinity site. Applying this strategy to 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug for Alzheimer's disease, we obtained alkylene linked bis-THA analogs. These analogs were up to 10,000-fold more selective and 1,000-fold more potent than THA in inhibiting rat AChE and yet required one simple reaction to synthesize. Additionally, alkylene linked benzyl-THA analogs were developed to examine the specificity of the docking-derived low affinity THA peripheral site in AChE. The present work and our previous computational studies strongly suggest that a low affinity THA peripheral site exists in AChE. This peripheral site provides a structural basis for design of improved cholinesterase ligands for treating Alzheimer's disease and for other health-related purposes.