title: Copper imbalances in ruminants and humans: unexpected common ground.
abstract: Ruminants are more vulnerable to copper deficiency than humans because rumen sulfide generation lowers copper availability from forage, increasing the risk of conditions such as swayback in lambs. Molybdenum-rich pastures promote thiomolybdate (TM) synthesis and formation of unabsorbable Cu-TM complexes, turning risk to clinical reality (hypocuprosis). Selection pressures created ruminant species with tolerance of deficiency but vulnerability to copper toxicity in alien environments, such as specific pathogen-free units. By contrast, cases of copper imbalance in humans seemed confined to rare genetic aberrations of copper metabolism. Recent descriptions of human swayback and the exploratory use of TM for the treatment of Wilson's disease, tumor growth, inflammatory diseases, and Alzheimer's disease have created unexpected common ground. The incidence of pre-hemolytic copper poisoning in specific pathogen-free lambs was reduced by an infection with Mycobacterium avium that left them more responsive to treatment with TM but vulnerable to long-term copper depletion. Copper requirements in ruminants and humans may need an extra allowance for the "copper cost" of immunity to infection. Residual cuproenzyme inhibition in TM-treated lambs and anomalies in plasma copper composition that appeared to depend on liver copper status raise this question "can chelating capacity be harnessed without inducing copper-deficiency in ruminants or humans?" A model of equilibria between exogenous (TM) and endogenous chelators (e.g., albumin, metallothionein) is used to predict risk of exposure and hypocuprosis; although risk of natural exposure in humans is remote, vulnerability to TM-induced copper deficiency may be high. Biomarkers of TM impact are needed, and copper chaperones for inhibited cuproenzymes are prime candidates.
authors.affiliation: Moredun Foundation, Penicuik, Scotland. suttle_hints@hotmail.com
authors.forename: Neville F
authors.initials: NF
authors.lastname: Suttle
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002614:Chelating Agents / Q000009:adverse effects / Q000627:therapeutic use; D003300:Copper / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D003677:Deficiency Diseases / Q000139:chemically induced* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006527:Hepatolenticular Degeneration / Q000188:drug therapy; D006801:Humans; D007239:Infections / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D008982:Molybdenum / Q000009:adverse effects / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D009751:Nutritional Requirements; D012418:Ruminants
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate