Accession Number : ADA314678

Title :   Studies on the Molecular Dissection of Human Cholinesterase Variants and their Genomic Origins.

Descriptive Note : Final rept. 1 Jun 94-30 May 96,

Corporate Author : HEBREW UNIV JERUSALEM (ISRAEL)

Personal Author(s) : Soreq, Hermona

PDF Url : ADA314678

Report Date : JUN 1996

Pagination or Media Count : 279

Abstract : To evaluate the capacity of overexpressed recombinant human cholinesterases or mutated variants thereof to confer protection against anti-cholinesterase toxicity, we employed transiently transgenic Xenopus laevis tadpoles and stably transgenic mice. Normal and mutant variants of butyrylcholinesterase (BuChE) revealed partially overlapping binding sites for several inhibitors and demonstrated the involvement of the oxyanion hole in BuChE catalysis. In the developing tadpoles the isoform of AChE, which terminates with the 3'-exon 6, was efficiently accumulated in neuromuscular junctions and conferred resistance to the organophosphate paraoxon. In transgenic mice, exon 6-terminated AChE, under control of its authentic promoter, accumulated in CNS synapses and conferred resistance to paraoxon and several cholinergic agonists, but caused progressive deterioration in both neuromotor and cognitive functioning. Finally, in a human patient carrying the "atypical'1 (D7OG) gene for BuChE, we observed adverse responses to prophylactic doses of the carbamate pyridostigmine and from this and in vitro studies predicted a generalized genetic predisposition to anti- cholinesterase therapies, including that approved for the treatment of Alzheimer's disease.

Descriptors :   *TOXICITY, *IN VITRO ANALYSIS, *ACETYLCHOLINESTERASE, *CHOLINESTERASE, AMPHIBIANS, HUMANS, MOLECULES, RESISTANCE, MUTATIONS, VARIATIONS, RESPONSE, ADVERSE CONDITIONS, DOSAGE, THERAPY, CATALYSIS, MUSCLES, PATIENTS, MICE, BINDERS, JUNCTIONS, SYNAPSE, DETERIORATION, INSECTICIDES, CENTRAL NERVOUS SYSTEM, NERVES, ORGANOPHOSPHATES, PYRIDINES, PREVENTIVE MEDICINE, PHOSPHATES, CARBAMATES, NITROPHENOLS, DISSECTION.

Subject Categories : Biochemistry
      Toxicology

Distribution Statement : APPROVED FOR PUBLIC RELEASE