Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats

doi:10.1016/S0162-0134(00)80000-8

Journal of Inorganic Biochemistry

Volume 14, Issue 3, 1981, Pages 189-207

https://doi.org/10.1016/S0162-0134(00)80000-8 Get rights and content

Abstract

Species differences in the response to dietary MoO₄²⁻ as a metabolic antagonist of Cu are considered briefly. Suggestions that (i) the potency of MoO₄²⁻ as a Cu antagonist is enhanced by normally innocuous dietary concentrations of S²⁻ and (ii) that MoS₄²⁻ may be a more effective antagonist than either MoO₄²⁻ or S²⁻ were investigated in a series of studies with rats. Diets including MoS₄²⁻ but not of MoO₄²⁻ or S²⁻ alone promoted a decline in hepatic Cu and ceruloplasmin activity and induced clinical signs of Cu deficiency. Evidence of concurrent anomalies in the partition of Cu between tissues and in the distribution of Cu between proteins of plasma and kidney cytosol suggested that such effects were partly attributable to the development of systemic defects in Cu metabolism. The relationship of such findings to the suggested involvement of MoS₄²⁻ or its derivatives in the etiology of Mo-induced Cu deficiency in ruminant animals is considered.

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Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease
2024, Journal of Hepatology
In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion.
In a double-blind randomized setting, hepatic ⁶⁴Cu activity was examined after orally administered ⁶⁴Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral ⁶⁴Cu was administered one hour after the final TTM dose. Changes in hepatic ⁶⁴Cu activity reflected changes in intestinal ⁶⁴Cu uptake. Additionally, in four patients with WD, the distribution of ⁶⁴Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. ⁶⁴Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder ⁶⁴Cu activity was taken as evidence of increased biliary ⁶⁴Cu excretion.
In healthy volunteers, TTM reduced intestinal ⁶⁴Cu uptake by 82% 15 hours after the oral ⁶⁴Cu dose. In patients with WD, gallbladder ⁶⁴Cu activity was negligible before and after TTM, while TTM effectively retained ⁶⁴Cu in the blood, significantly reduced hepatic ⁶⁴Cu activity at all time-points and significantly reduced cerebral ⁶⁴Cu activity two hours after the intravenous ⁶⁴Cu dose.
While we did not show an increase in biliary excretion of ⁶⁴Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal ⁶⁴Cu uptake and retained ⁶⁴Cu in the blood stream, limiting the exposure of organs like the liver and brain to ⁶⁴Cu.
Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study builds on our understanding of human copper metabolism and the mechanism of action of TTM.
Effects of Molybdate and Tetrathiomolybdate Supplementation of Drinking Water on Immature Rats Infected with Nippostrongylus brasiliensis. 2. Copper Status and Tissue Molybdenum Accretion
2022, Journal of Comparative Pathology
Citation Excerpt :
Acute exposure of yeast cells to MoS4 in vitro (Alvarez et al, 2010) and rat livers to parenteral MoS4 (Ogra et al, 2000) caused Cu and Mo to accumulate in a molar ratio close to 4:1. Low dietary exposure to MoS4 generally lowers Cu status in all species (Suttle, 2012a) and can induce clinical abnormalities in rats (Spence et al, 1980; Mills et al, 1981a) but chronic exposure via drinking water increased Cu status in most tissues. The contrast probably arises because dietary MoS4 readily forms complexes with dietary Cu and fibre in and beyond the stomach and little is absorbed (Mills et al, 1981b).
Molybdate (MoO₄) and tetrathiomolybdate (MoS₄) supplementation of rats via drinking water had opposite effects on the establishment of Nippostrongylus brasiliensis larvae but both induced hypercupraemia, temporarily inhibited activities of superoxide dismutase in liver and duodenum after infection and enlarged the femoral head. Effects of MoO₄ and MoS₄ on activities of caeruloplasmin oxidase (CpO) in plasma, erythrocyte superoxide dismutase (ESOD) and tissue copper (Cu) and molybdenum (Mo) were compared to test the hypothesis that species lacking a rumen can thiolate MoO₄. Three groups of 18 immature Wistar rats were given Mo (70 mg/L as MoO₄) or MoS₄ (5 mg/L) via drinking water or remained untreated; all received a commercial, cubed diet and 12 from each group were infected with larvae of N. brasiliensis. Rats were killed 7–9 days later and liver, kidney, spleen, heart, muscle (quadriceps), brain and bone (femur) removed for Cu and Mo analysis. Plasma Cu was greatly increased by MoO₄ and MoS₄, without changing CpO activity, but the effect was more variable with MoO₄ and accompanied by a smaller decrease in ESOD. Tissue Cu and Mo were increased by MoS₄ in all tissues examined except brain and bone, correlating with plasma Cu and with each other; relationships were strongest in spleen, followed by kidney. MoO₄ also increased soft tissue Cu and Mo but increases were generally smaller than those induced by MoS₄ and correlations between the two elements and with plasma Cu generally weaker. Since hypercupraemia and correlated increases in liver and kidney Cu and Mo are characteristic of systemic thiomolybdate (TM) exposure, we conclude that MoO₄ was partially thiolated to give a different TM profile from that produced by MoS₄. The pathophysiological significance of systemic exposure to di- and tri-TM merits investigation in non-ruminants as agents of chelation therapy and in ruminants as agents of short-lived TM toxicity on Mo-rich pastures.
Copper-related diseases: From chemistry to molecular pathology
2010, Coordination Chemistry Reviews
The aim of this review is to give a general view on the current status of the scientific basis for the role of copper in human health and disease, outlining the roles of copper in human metabolism and bioenergetics, its coordination chemistry as well as its biological ligands involved in the multiple steps of metal assimilation and distribution. Copper bioavailability depends on four main factors: (1) the absorption of copper from the gastrointestinal tract; (2) copper transport in the portal blood; (3) the extraction of copper by hepatocytes from the portal blood supply; (4) copper uptake by peripheral tissues and by the central nervous system. The most important copper pumps, providing a permeation pathway for copper ions in man, such as hCTR1, hCTR2, DMT1, ATP7A, ATP7B, and MURR1, are extensively discussed. Different theories on the putative role of ceruloplasmin in copper transport in blood are presented. Data on interactions among other trace elements and copper, from the level of enterocyte to other systems in the body, are also shown. Finally, the function of different drugs, chelators and non-chelating agents, utilized in clinical practice in the therapy of Wilson's disease is treated, in particular the “reductive chelation” of penicillamine is discussed.
Drug development for orphan diseases in the context of personalized medicine
2009, Translational Research
Citation Excerpt :
TM had seen veterinary use; it was an excellent acute treatment to save copper poisoned sheep who usually die of liver failure.26 TM has a unique mechanism of action, which forms a 3-way complex with copper and protein.27-29 Given with meals, it binds food copper and protein, as well as endogenously secreted copper and protein, and it prevents its absorption.30
Orphan diseases are diseases that are found in less than 200,000 patients in the United States, which is the cutoff point for the number of patients for a drug to be profitable. Because many thousands of orphan diseases exist in the aggregate (about 20 to 30 million Americans have orphan diseases), these patients are disenfranchised from drug development by the pharmaceutical industry. Orphan drugs are a large part of personalized medicine. The orphan diseases are often so rare that a physician may observe only 1 case a year or less. So proper treatment is a personalized encounter between doctor and patient. Academic physician-scientists have tried to fill this therapy vacuum by working on developing orphan drugs. But many disincentives are involved, which include career disincentives, lack of funding, and the multiple areas of expertise that are required. Positive developments include formation of the National Organization for Rare Diseases, the Orphan Drug Act, the development of a grant program to fund orphan drug development, the formation of the National Institutes of Health Office of Rare Diseases, and the passage of orphan drug legislation by other countries. Progress has increased, but the 300 orphan drugs and devices approved in the last 25 years are still only a drop in the bucket compared with the many thousands of orphan diseases. I believe we must do better. I present my own 2 examples of the positive and the negative aspects of orphan drug development, and I end this article by giving recommendations on how we might succeed both in developing more orphan drugs and in rescuing the pharmaceutical industry from its impending economic collapse.
Treatment of Wilson's disease with tetrathiomolybdate: V. control of free copper by tetrathiomolybdate and a comparison with trientine
2009, Translational Research
It has become clear that serum “free” copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance—if they worsen neurologically as often happens with penicillamine or trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than trientine. In the trientine arm of study 2, mean free copper levels actually went up during trientine therapy. The 5 patients who neurologically worsened on trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way “away from food” tetrathiomolybdate was given.
Efficacy of tetrathiomolybdate in a mouse model of multiple sclerosis
2008, Translational Research
Tetrathiomolybdate (TM) is a potent anticopper drug developed for Wilson's disease. We have found multiple efficacious results from decreasing copper levels with TM in mouse models of disease, using serum Cp as a surrogate marker of copper status and targeting Cp values of 20% to 50% of baseline. We have found efficacious results of TM therapy in mouse models of fibrosis; inflammation; damage from exogenous agents, such as acetaminophen and doxorubicin; and immune-modulated diseases, such as concanavalin A hepatitis, collagen II-induced arthritis, and the non-obese diabetic (NOD) mouse model of type I diabetes. In the current study, we examine TM efficacy in the EAE mouse model of multiple sclerosis (MS). We find that clinical scores of neurologic damage are significantly inhibited by TM therapy, whether therapy is started before MS-inducing antigen administration or after symptoms from antigen administration develop. Furthermore, we find that experimental autoimmune encephalomyelitis (EAE) treatment produces a marked increase of oxidant damage, as measured by urine isoprostane levels, and TM suppresses these isoprostane increases strongly and significantly. Finally, we find marked increases of inflammatory and immune-related cytokines in this model, and we find that TM strongly and significantly suppresses these increases.

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Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats

Abstract

J. Nutr.

J. Nutr.

J. Nutr.

J. Nutr.

J. Nutr.

Clin. Chem. Acta

J. Comp. Path.

J. Inorg. Bio.

J. Nutr.

Anal. Biochem.

J. Comp. Path.

J. Biol. Chem.

Res. Vet. Sci.

Proc. Nutr. Soc.

Br. J. Nutr

Proc. Aust. Soc. Anim. Prod.

J. Agric. Sci. Camb.