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Wilson's disease is a rare autosomal recessive disease characterised by the deposition of copper in the brain, liver; cornea, and other organs. The overload of copper inevitably leads to progressive liver and neurological dysfunction. Copper overload in patients with Wilson's disease is caused by impairment to the biliary route for excretion of dietary copper A combination of neurological, psychiatric and hepatic symptoms can make the diagnosis of Wilson's disease challenging. Most symptoms appear in the second and third decades of life. The disease affects between one in 30,000 and one in 100,000 individuals, and is fatal if left untreated. Five drugs are currently available to treat Wilson's disease: British Anti-Lewisite; D-penicillamine; trientine; zinc sulfate or acetate; and ammonium tetrathiomolybdate. Each drug can reduce copper levels and/or transform copper into a metabolically inert and unavailable form in the patient. The discovery and introduction of these five drugs owes more to the inspiration of a few dedicated physicians and agricultural scientists than to the resources of the pharmaceutical industry.

Rat hepatocytes were cultured for 70 hours with a series of four isomeric octyl and five isomeric hexyl phthalate monoesters, and their effects on peroxisomal fatty acid beta-oxidation (palmitoyl-CoA oxidation) and carnitine acetyltransferase activities determined. All nine monoesters produced dose-related increases in enzyme activities and marked quantitative compound potency differences were observed. Generally octyl isomers were more potent than hexyl isomers and 2- and 3-ethyl substituted isomers were more potent than their straight chain and 1-ethyl substituted analogs. For example, mono(2-ethylhexyl)phthalate was more potent than mono(1-ethylhexyl)phthalate, and this was also observed after oral administration of the two isomers to rats for seven days. The cell culture data for induction of palmitoyl-CoA oxidation were used to generate quantitative structure-activity relationships. Relatively poor correlations were observed between biological activity and simple hydrophobic parameters, but a good correlation was obtained when compound electronic structural parameters, obtained by molecular orbital calculations, were employed. These studies demonstrate relationships between biological activity and chemical structure for a series of phthalate monoesters and indicate the potential usefulness of primary rat hepatocyte cultures to screen compounds for peroxisome proliferation.

Wilson's disease (hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of copper metabolism leading to copper accumulation in the liver and extrahepatic organs such as the brain and cornea. Patients may present with combinations of hepatic, neurological and psychiatric symptoms. Copper is the therapeutic target for the treatment of Wilson's disease. But how did copper come to be linked with Wilson's disease? The answer encompasses a study of enzootic neonatal ataxia in lambs in the 1930s, the copper-chelating properties of British Anti-Lewisite, and the chemical analysis for copper of the organs of deceased Wilson's disease patients in the mid-to-late 1940s. Wilson's disease is one of a number of copper-related disorders where loss of copper homeostasis as a result of genetic, nutritional or environmental factors affects human health.

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