ABSTRACT
Niemann-Pick C disease (NPC) is an autosomal recessive lysosomal storage disorder resulting from mutations in the NPC1 (95% of cases) or NPC2 genes. Disturbance of copper homeostasis has been reported in NPC1 disease. In this study we have used whole-body positron emission tomography (PET) and brain electronic autoradiography with copper-64 (64Cu), in the form of the copper(II) bis(thiosemicarbazonato) complex 64Cu-GTSM, to image short-term changes in copper trafficking after intravenous injection in a transgenic mouse model of NPC1 disease. 64Cu-GTSM is taken up in all tissues and dissociates rapidly inside cells, allowing monitoring of the subsequent efflux and redistribution of 64Cu from all tissues. Significantly enhanced retention of 64Cu radioactivity was observed in brain, lungs and blood at 15 h post-injection in symptomatic Npc1-/- transgenic mice compared to wildtype controls. The enhanced retention of 64Cu in brain was confirmed by electronic autoradiography, particularly in the midbrain, thalamus, medulla and pons regions. Positron emission tomography imaging with 64Cu in selected chemical forms could be a useful diagnostic and research tool for the management and understanding of NPC1 disease.
Subject(s)
Copper Radioisotopes/metabolism , Copper Radioisotopes/pharmacokinetics , Disease Models, Animal , Niemann-Pick Disease, Type C/metabolism , Positron-Emission Tomography , Animals , Coordination Complexes/administration & dosage , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Coordination Complexes/pharmacokinetics , Copper Radioisotopes/administration & dosage , Injections, Intravenous , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Transgenic , Thiosemicarbazones/administration & dosage , Thiosemicarbazones/chemistry , Thiosemicarbazones/metabolism , Thiosemicarbazones/pharmacokineticsABSTRACT
This review describes the life of Sir John Cornforth AC CBE FRS, who was awarded the Nobel Prize for Chemistry in 1975. It covers his early life in Australia, his work in Oxford, the National Institute for Medical Research, the Milstead Laboratory of Chemical Enzymology and the University of Sussex, together with the contributions made by his wife, Lady Rita Cornforth.
Subject(s)
Chemistry/history , Australia , History, 20th Century , History, 21st Century , Nobel Prize , United KingdomABSTRACT
Sir John Cornforth work on the synthesis of cholesterolandpenicillamine, on the chemistry of oxazoles, the stereochemistry of the synthesis of alkenes, the synthesis of abscisic acid and of dibenzophospholes as mimics of enzyme action, is reviewed.
Subject(s)
Chemistry Techniques, Synthetic/history , Chemistry/history , Enzymes/chemistry , History, 20th Century , History, 21st Century , Penicillins/chemistry , Sterols/chemistryABSTRACT
Sir John Cornforth's work on the stereochemistry of enzyme reactions involved in the biosynthesis of squalene and cholesterol and in the formation and metabolism of a chiral methyl group in acetyl co-enzyme A, is reviewed.
Subject(s)
Chemistry/history , Biocatalysis , Cholesterol/biosynthesis , Cholesterol/metabolism , History, 20th Century , History, 21st CenturyABSTRACT
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.
Subject(s)
Chelating Agents/therapeutic use , Copper/metabolism , Hepatolenticular Degeneration/drug therapy , Hepatolenticular Degeneration/metabolism , Animals , Brain/metabolism , Copper/deficiency , Cornea/metabolism , Hepatolenticular Degeneration/veterinary , Humans , Liver/metabolism , Models, Biological , Sheep , Sheep Diseases/metabolismABSTRACT
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.
