Molybdenum Abstracts 2

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Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy.
            (Abumrad et al., 1981) Download
This report describes a patient suffering from intolerance to L-methionine, while on prolonged total parenteral nutrition. Biochemical abnormalities included high plasma methionine (I 10 to 130 tmol/L. normal 10 to 55 jimol/L) and low serum uric acid levels (0.5 to 1.4 mg/dl) associated with increased urinary excretion of sulfite (strong positive colonimetnic reaction on Machery Nagel strips versus absent reaction in controls), thiosulfate (4.4 to 9.5 mM/d day or 30 to 50 of total sulfur excretion versus normal = 0.4 ± 0. 1 mM/day or <2%). hypoxanthine (150 to 750 mg/24 h, normal <50 mgI 24 h) and xanthine (700 to 2100 mg124 h. normal <SO mg124 h), with a decreased urinary excretion of uric acid (<100 mg124 h. normal 300 to 520 mg124 h) and inorganic sulfate (2.9 to 5.5 mMlday or 10 to 40 of total sulfur excretion versus ± 181.3.2 mMlday in normal or 80 oftotal sulfur excretion). These abnormalities indicated that the underlying defect in sulfur amino acid metabolism occurred at the level of transformation of sulfite to sulfate. while that in uric acid production was at the level of transformation of xanthine and hypoxanthine to uric acid. The two enzymes catalyzing these reactions are sulfite oxidase, and xanthine oxidase, two metallo-enzymes containing molybdenum as part of their prosthetic groups. Treatment with ammonium molybdate (300 µg/day) improved the clinical condition, reversed the sulfur handling defect and normalized uric acid production.

Molybdenum--is it an essential trace metal
            (Abumrad, 1984) Download
Molybdenum, with an atomic number of 42, is presently considered an essential trace element that participates in a number of enzymatic reactions in many microorganisms and mammals. There are several known molybdenum-containing enzymes: xanthine oxidase/dehydrogenase, aldehyde oxidase, and sulfite oxidase.


 

Effects of molybdate and pentachlorophenol on the sulfation of acetaminophen.
            (Boles and Klaassen, 2000) Download
Pentachlorophenol (PCP) is an inhibitor of phenol-sulfotransferases and has been used to ascertain the role of sulfation in toxicology. Recently, molybdate has been shown to inhibit the sulfation of various chemicals by decreasing hepatic concentrations of the cosubstrate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS). The purpose of this study was to compare the effectiveness of these two chemicals in inhibiting the sulfation of various doses of acetaminophen (AA) in the rat. PCP (40 micromol/kg) decreased the 2-h combined biliary and urinary excretion of AA-sulfate by 78, 83, 84, and 47% of the 0.1, 0.3, 1, and 3 mmol/kg doses of AA, respectively. Molybdate (7.5 mmol/kg) decreased the sulfation of these same doses of AA by 50, 65, 62, and 81%, respectively. These data indicate that PCP is more effective in decreasing the sulfation of low than high doses of AA, which may result from less AA, at lower doses, to compete with PCP for sulfotransferases. Conversely, molybdate is more effective in decreasing sulfation of high rather than low doses of AA because molybdate decreases sulfate availability and decreases PAPS synthesis. More PAPS is required for the sulfation of high than low doses of AA. Therefore, PCP inhibits sulfation more effectively at low doses of AA when sulfation is limited by sulfotransferases, and molybdate inhibits sulfation more effectively at high doses of AA when sulfation is limited by PAPS.

Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics.
            (Bueno et al., 2013) Download
SIGNIFICANCE:  Pulmonary arterial hypertension (PAH) is a disorder characterized by increased pulmonary vascular resistance and mean pulmonary artery pressure leading to impaired function of the right ventricle, reduced cardiac output, and death. An imbalance between vasoconstrictors and vasodilators plays an important role in the pathobiology of PAH. RECENT ADVANCES:  Nitric oxide (NO) is a potent vasodilator in the lung, whose bioavailability and signaling pathway are impaired in PAH. It is now appreciated that the oxidative product of NO metabolism, the inorganic anion nitrite (NO(2)(-)), functions as an intravascular endocrine reservoir of NO bioactivity that can be reduced back to NO under physiological and pathological hypoxia. CRITICAL ISSUES:  The conversion of nitrite to NO is controlled by coupled electron and proton transfer reactions between heme- and molybdenum-containing proteins, such as hemoglobin and xanthine oxidase, and by simple protonation and disproportionation, and possibly by catalyzed disproportionation. The two major sources of nitrite (and nitrate) are the endogenous L-arginine-NO pathway, by oxidation of NO, and the diet, with conversion of nitrate from diet into nitrite by oral commensal bacteria. In the current article, we review the enzymatic formation of nitrite and the available data regarding its use as a therapy for PAH and other cardiovascular diseases. FUTURE DIRECTIONS:  The successful efficacy demonstrated in several animal models and safety in early clinical trials suggest that nitrite may represent a promising new therapy for PAH.

The role of aldehyde oxidase in drug metabolism.
            (Garattini and Terao, 2012) Download
INTRODUCTION:  Aldehyde oxidases (AOXs) are molybdo-flavoenzymes with complex evolutionary profiles, as the number and types of active AOX genes vary according to the animal species considered. Humans and higher primates have a single functional AOX1 gene, while rodents are endowed with four AOXs. Along with the endoplasmic cytochrome P450 system (CYP450), cytoplasmic AOX1 is the major enzyme involved in the hepatic phase I metabolism of numerous xenobiotics. AREAS COVERED:  The authors review literature to highlight the fact that aldehydes are not the only AOX substrates, as aza- and oxo-heterocycles, that represent the scaffold of many drugs, are also oxidized efficiently by these enzymes. Additionally, the ndefine the different complements of AOX isoenzymes expressed in humans and animal models used in drug metabolism studies and discuss the implications. Furthermore, the authors report on human AOX1 allelic variants that alter the activity of this enzyme. Finally, they discuss the factors of potential importance in controlling the functional activity of AOX1. EXPERT OPINION:  There is evidence for an increasing relevance of AOX1 in the metabolism and clearance of new drugs, as measures aiming at controlling CYP450-dependent metabolism of prospective therapeutic agents are becoming routine. This calls for investigations into the biology, catalytic properties and substrate specificity of human AOX1.

Inborn errors of molybdenum metabolism: combined deficiencies of sulfite oxidase and xanthine dehydrogenase in a patient lacking the molybdenum cofactor.
            (Johnson et al., 1980) Download
A patient suffering from a combined deficiency of sulfite oxidase (sulfite dehydrogenase; sulfite:ferricytochrome c oxidoreductase, EC 1.8.2.1) and xanthine dehydrogenase (xanthine:NAD+ oxidoreductase, EC 1.2.1.37) is described. The patient displays severe neurological abnormalities, dislocated ocular lenses, and mental retardation. Urinary excretion of sulfite, thiosulfate, S-sulfocysteine, taurine, hypoxanthine, and xanthine is increased in this individual, while sulfate and urate levels are drastically reduced. The metabolic defect responsible for loss of both enzyme activities appears to be at the level of the molybdenum cofactor common to the two enzymes. Immunological examination of a biopsy sample of liver tissue revealed the presence of the xanthine dehydrogenase protein in near normal amounts. Sulfite oxidase apoprotein was not detected by a variety of immunological techniques. The plasma molybdenum concentration was normal; however, hepatic content of molybdenum and the storage pool of active molybdenum cofactor present in normal livers were below the limits of detection. Fibroblasts cultured from this patient failed to express sulfite oxidase protein or activity, whereas those from the parents and healthy brother of the patient expressed normal levels of this enzyme.

Environmental exposure to metals and male reproductive hormones: circulating testosterone is inversely associated with blood molybdenum
            (Meeker et al., 2010) Download
OBJECTIVE: To explore associations between exposure to metals and male reproductive hormone levels. DESIGN: Cross-sectional epidemiology study with adjustment for potential confounders. SETTING: University Medical Center. PATIENT(S): Men recruited through two infertility clinics in Michigan. INTERVENTION(S): Metal concentrations and reproductive hormone levels were measured in blood samples collected from 219 men. MAIN OUTCOME MEASURE(S): Serum FSH, LH, inhibin B, T, and sex hormone-binding globulin levels. RESULT(S): Cadmium, copper, and lead were all significantly or suggestively positively associated with T when modeled individually, findings that are consistent with limited previous human and animal studies. Conversely, molybdenum was associated with reduced T. A significant inverse trend between molybdenum and T remained when additionally considering other metals in the model, and a positive association between T and zinc was also found. Finally, in exploratory analysis there was evidence for an interaction between molybdenum and zinc, whereby high molybdenum was associated with a 37% reduction in T (relative to the population median level) among men with low zinc. CONCLUSION(S): Although reductions in T and reproductive toxicity after molybdenum exposure have been previously demonstrated in animal studies, more research is needed to determine whether molybdenum poses a risk to human reproductive health.

A case report of acute human molybdenum toxicity from a dietary molybdenum supplement--a new member of the "Lucor metallicum" family.
            (Momcilović, 1999) Download
The paper gives a brief review of human molybdenum metabolism and toxicity and presents the first known case of acute clinical poisoning with molybdenum from the dietary molybdenum (Mo) supplement in a male patient in late thirties. In over 18 days, the patient had consumed a cumulative dose of 13.5 mg Mo (300-800 micrograms Mo/day). Followed the development of acute psychosis with visual and auditory hallucinations, a series of petit mal seizures, and one life threatening grand mal attack. The symptoms remitted several hours after the start of chelation therapy with calcium ethylene diamine tetraacetic acid (CaEDTA). A battery of neuropsychological tests and Spectral Emission Computer Tomography demonstrated evident frontal cortical damage of the brain. One year after the Mo poisoning, the patient was diagnosed toxic encephalopathy with executive deficiencies, learning disability, major depression, and post-traumatic stress disorder. The paper strongly advocates issuance of and strict adherence to written warnings on the instruction labels not to mix potentially harmful neurotoxic substances, such as molybdenum, with other nutriceuticals and to instructions stating maximal single and cumulative doses. Molybdenum is a new and unwelcome member of the "metal madness" family.

Molybdenum kinetics in men differ during molybdenum depletion and repletion.
            (Novotny and Turnlund, 2006) Download
In this study we developed an expanded compartmental model of molybdenum (Mo) kinetics to determine rates of molybdenum distribution during molybdenum depletion and repletion. The model was based on a clinical study in which 4 men consumed a low-molybdenum diet of 22 microg/d (0.23 micromol/d) for 102 d, followed by a high molybdenum diet of 467 microg/d (4.9 micromol/d) for 18 d. Stable isotopes 100Mo and 97Mo were administered orally and intravenously, respectively, at several time points during the study, and serial samples of plasma, urine, and feces were analyzed for 100Mo, 97Mo, and total Mo. Based on plasma, urine, and fecal molybdenum levels, kinetic parameters of distribution and elimination were determined. The rates of molybdenum distribution and elimination were different during depletion and repletion. During high intake, urinary molybdenum excretion was greater than during low intake. In addition, fractional tissue storage of molybdenum was lower during high intake than during low intake. This suggests that low intake results in an adaptation to conserve body Mo, and that high intake results in an adaptation to eliminate Mo. The model also suggested that food-bound molybdenum was approximately 16% less bioavailable than purified Mo. Finally, under the conditions of this study, the model suggested that an intake of 43 microg/d (0.45 micromol/d) would be sufficient to maintain plasma molybdenum levels at steady state. This is a minimum estimate because subjects in this study were in a molybdenum-sparing state. These findings provide an understanding of the adaptations in molybdenum metabolism that take place during depletion and repletion.


 

Chemical nature and reaction mechanisms of the molybdenum cofactor of xanthine oxidoreductase.
            (Okamoto et al., 2013) Download
Xanthine oxidoreductase (XOR), a complex flavoprotein, catalyzes the metabolic reactions leading from hypoxanthine to xanthine and from xanthine to urate, and both reactions take place at the molybdenum cofactor. The enzyme is a target of drugs for therapy of gout or hyperuricemia. We review the chemical nature and reaction mechanisms of the molybdenum cofactor of XOR, focusing on molybdenum-dependent reactions of actual or potential medical importance, including nitric oxide (NO) synthesis. It is now generally accepted that XOR transfers the water-exchangeable -OH ligand of the molybdenum atom to the substrate. The hydroxyl group at OH-Mo(IV) can be replaced by urate, oxipurinol and FYX-051 derivatives and the structures of these complexes have been determined by xray crystallography under anaerobic conditions. Although formation of NO from nitrite or formation of xanthine from urate by XOR ischemically feasible, it is not yet clear whether these reactions have any physiological significance since the reactions are catalyzed at a slow rate even under anaerobic conditions.

Inhibitory effects of flavonoids on molybdenum hydroxylases activity.
            (Rashidi and Nazemiyeh, 2010) Download
Molybdenum hydroxylases, aldehyde oxidase and xanthine oxidase, are metalloflavoproteins that catalyze both oxidation and reduction of a broad range of drugs and other xenobiotics indicating the importance of these enzymes in drug oxidation, detoxification and activation. Both enzymes are also involved in some physiological processes and also the metabolism of some endogenous compounds which may indicate their important roles in in vivo conditions. Superoxide radical and hydrogen peroxide produced during molybdenum hydroxylases-catalyzed reactions may be relevant in various disease conditions. Therefore, the interference with the function of molybdenum hydroxylases could be of great importance. Flavonoids are a large group of polyphenolic compounds that are able to interfere with xanthine oxidase and aldehyde oxidase function. As flavonoids are consumed in high content in our daily life, their potential to interfere with molybdenum hydroxylases could be a serious concern for consumer safety. However, the subject has not received enough attention and has usually been overshadowed by that of cytochrome P450 as the most important drug metabolizing enzyme system. The present review focuses on the different aspects of flavonoids interaction with molybdenum hydroxylases considering literature published mainly in the last 2 decades. The review also provides insight into some research areas that may offer a great potential for future studies.


Molybdenum exposure and semen quality: how robust is the evidence of an effect
            (Sorahan and Sullivan, 2009) Download
Comment on Meeker 2010

Molybdenum absorption, excretion, and retention studied with stable isotopes in young men during depletion and repletion.
            (Turnlund et al., 1995) Download
A study of molybdenum absorption, excretion, and balance was conducted in four young men fed a low-molybdenum diet (22 micrograms/d) for 102 d followed by 18 d of the same diet supplemented to contain 467 micrograms/d. The study was conducted to determine the minimum dietary molybdenum requirement of healthy young men. Stable isotopes of molybdenum were used as tracers. 100Mo was fed four times during the study, 97Mo was infused twice, and 94Mo was used as an isotopic diluent to quantify the molybdenum isotopes and total molybdenum in complete urine and fecal collections and in the diets. The study demonstrated that subjects could not consistently attain balance with the low-molybdenum diet, but balance improved with time, and no signs of molybdenum deficiency were observed. Molybdenum was very efficiently absorbed at both intakes of dietary molybdenum and urinary excretion increased as dietary molybdenum increased. Molybdenum turnover was significantly slower when dietary molybdenum was low. We estimate from these results that the minimum dietary molybdenum requirement is approximately 25 micrograms/d or possibly less. This suggests that the lower end of the recommended range could be less than the current recommended amount of 75 micrograms/d.

Alteration of drug metabolizing enzymes in sulphite oxidase deficiency.
            (Tutuncu et al., 2012) Download
The aim of this study was to investigate the possible effects of sulphite oxidase (SOX, E.C. 1.8.3.1) deficiency on xenobiotic metabolism. For this purpose, SOX deficiency was produced in rats by the administration of a low molybdenum diet with concurrent addition of 200 ppm tungsten to their drinking water. First, hepatic SOX activity in deficient groups was measured to confirm SOX deficiency. Then, aminopyrine N-demethylase, aniline 4-hydroxylase, aromatase, caffeine N-demethylase, cytochrome b5 reductase, erythromycin N-demethylase, ethoxyresorufin O-deethylase, glutathione S-transferase, N-nitrosodimethylamine N-demethylase and penthoxyresorufin O-deethylase activities were determined to follow changes in the activity of drug metabolizing enzymes in SOX-deficient rats. Our results clearly demonstrated that SOX deficiency significantly elevated A4H, caffeine N-demethylase, erythromycin N-demethylase and N-nitrosodimethylamine N-demethylase activities while decreasing ethoxyresorufin O-deethylase and aromatase activities. These alterations in drug metabolizing enzymes can contribute to the varying susceptibility and response of sulphite-sensitive individuals to different drugs and/or therapeutics used for treatments.

Assessment of molybdenum toxicity in humans.
            (Vyskocil and Viau, 1999) Download
In an attempt to define a tolerable daily intake (TDI) for molybdenum based on a toxicological risk analysis approach, a large literature survey was conducted. In man, absorption of molybdenum after oral intake is in the range of 28-77% and urinary excretion is 17-80% of the total dose. A low order of toxicity of molybdenum compounds has been observed in humans. However, with the available data, it is not possible to calculate any dose-response or dose-effect relationships. Because molybdenum toxicity is associated with copper intake or depleted copper stores in the body, humans who have an inadequate intake of dietary copper or some dysfunction in their copper metabolism that makes them copper-deficient could be at greater risk of molybdenum toxicity. In the absence of relevant human studies, animal studies were evaluated for the derivation of the TDI. Effects of Mo on reproduction and foetal development were found to be critical effects observed in rats and mice. A dose-response relationship was observed in a study by Fungwe et al., with a 'no observed adverse effect' level (NOAEL) and a 'lowest observed adverse effect' level (LOAEL) of 0.9 and 1.6 mg Mo kg(-1) day(-1), respectively. Applying uncertainty factors of 10 for intraspecies and 10 for interspecies differences to the NOAEL, a TDI of 0.009 mg Mo kg(-1) day(-1) was calculated. The TDI is given a medium confidence rating. This TDI is more than double the upper limit of adequate intake for adolescents and adults that was derived from the Mo content of the average diet in the USA.

 

 


 

References

Abumrad, NN, et al. (1981), ‘Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy.’, Am J Clin Nutr, 34 (11), 2551-59. PubMedID: 6795919
Abumrad, NN (1984), ‘Molybdenum--is it an essential trace metal’, Bull N Y Acad Med, 60 (2), 163-71. PubMedID: 6426561
Boles, JW and CD Klaassen (2000), ‘Effects of molybdate and pentachlorophenol on the sulfation of acetaminophen.’, Toxicology, 146 (1), 23-35. PubMedID: 10773360
Bueno, M, et al. (2013), ‘Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics.’, Antioxid Redox Signal, 18 (14), 1797-809. PubMedID: 22871207
Garattini, E and M Terao (2012), ‘The role of aldehyde oxidase in drug metabolism.’, Expert Opin Drug Metab Toxicol, 8 (4), 487-503. PubMedID: 22335465
Johnson, JL, et al. (1980), ‘Inborn errors of molybdenum metabolism: combined deficiencies of sulfite oxidase and xanthine dehydrogenase in a patient lacking the molybdenum cofactor.’, Proc Natl Acad Sci U S A, 77 (6), 3715-19. PubMedID: 6997882
Meeker, J. D., et al. (2010), ‘Environmental exposure to metals and male reproductive hormones: circulating testosterone is inversely associated with blood molybdenum’, Fertil Steril, 93 (1), 130-40. PubMedID: 18990371
Momcilović, B (1999), ‘A case report of acute human molybdenum toxicity from a dietary molybdenum supplement--a new member of the “Lucor metallicum” family.’, Arh Hig Rada Toksikol, 50 (3), 289-97. PubMedID: 10649845
Novotny, JA and JR Turnlund (2006), ‘Molybdenum kinetics in men differ during molybdenum depletion and repletion.’, J Nutr, 136 (4), 953-57. PubMedID: 16549456
Okamoto, K, T Kusano, and T Nishino (2013), ‘Chemical nature and reaction mechanisms of the molybdenum cofactor of xanthine oxidoreductase.’, Curr Pharm Des, 19 (14), 2606-14. PubMedID: 23116398
Rashidi, MR and H Nazemiyeh (2010), ‘Inhibitory effects of flavonoids on molybdenum hydroxylases activity.’, Expert Opin Drug Metab Toxicol, 6 (2), 133-52. PubMedID: 20095789
Sorahan, T and FM Sullivan (2009), ‘Molybdenum exposure and semen quality: how robust is the evidence of an effect’, Environ Health Perspect, 117 (9), A386-7; author reply A387. PubMedID: 19750081
Turnlund, JR, et al. (1995), ‘Molybdenum absorption, excretion, and retention studied with stable isotopes in young men during depletion and repletion.’, Am J Clin Nutr, 61 (5), 1102-9. PubMedID: 7733035
Tutuncu, B, et al. (2012), ‘Alteration of drug metabolizing enzymes in sulphite oxidase deficiency.’, J Clin Biochem Nutr, 51 (1), 50-54. PubMedID: 22798713
Vyskocil, A and C Viau (1999), ‘Assessment of molybdenum toxicity in humans.’, J Appl Toxicol, 19 (3), 185-92. PubMedID: 10362269