Molybdenum: Definition, Synthesis, Absorption, Transport, and Distribution

Molybdenum a chemical element with the element symbol Mo and atomic number 42. In the periodic table it is in the 5th period and 6th subgroup (group VI B) or chromium group. Of all the elements of the 5th period, molybdenum has the highest melting point. Molybdenum, which is silver-colored in its pure form, is rare in the earth’s crust but is the most common redox-active metal in the oceans. It is one of the transition metals and is used in various stainless steel alloys for hardening and for catalyzing (accelerating) redox reactions (reduction/oxidation reactions). In its compounds, molybdenum occurs in the oxidation states MoII+, MoIII+, MoIV+, MoV+, and MoVI+, of which MoIV+ and MoVI+ are predominant. Molybdenum represents an essential (vital) trace element for almost all living organisms. The form that is bioavailable to the organism and metabolically active is the molybdate anion (MoO42-). This acts as a cofactor for some enzymes, a complex of molybdate and molybdopterin (heterocyclic compound) bound in the active site of the respective enzyme. The molybdenum-dependent enzyme systems of the human body include xanthine oxidase/dehydrogenase (purine degradation – conversion of hypoxanthine to xanthine and the latter to uric acid, which acts as an antioxidant in the blood plasma) occurring in the cytosol (liquid components of the cytoplasm) of the cell, sulfite oxidase localized in the mitochondria (“energy power plants” of the cells) (degradation of sulfur-containing amino acids, such as methionine and cysteinedetoxification of sulfite to sulfate) and cytosolic aldehyde oxidase (oxidation and detoxification (detoxification) of various nitrogen (N)-containing heterocyclic aromatic compounds, such as pyrimidines, purines and pteridines) [1, 4, 5, 10-13, 16, 19, 20, 21, 25, 31]. In the enzymatically catalyzed redox reactions, molybdenum – predominantly in the form of MoVI+ – assumes the function of electron transfer agent due to its ability to change oxidation states. Unlike other heavy metals, such as iron, copper, and manganese, molybdenum exhibits relatively low toxicity (toxicity). However, molybdenum dusts, compounds such as molybdenum (VI) oxide, and water-soluble molybdates, such as tetrathiomolybdate, may exhibit some toxicity at high doses because of their rapid and almost complete absorption (uptake through the intestine). In particular, individuals working in molybdenum mining, molybdenum manufacturing, or molybdenum processing plants are subject to increased exposure to molybdenum. Workers in a molybdenum-processing factory who inhaled dust containing molybdenum at a rate of about 10 mg Mo/day experienced slightly elevated serum uric acid levels and increased blood serum coeruloplasmin (an important glycoprotein in iron and copper metabolism) concentrations, as well as health complaints. However, it was not possible to conduct corresponding epidemiological studies because of the high turnover rate (replacement rate) of the workers. There is a lack of systematic and adequately designed studies to assess the risk of long-term elevated molybdenum intake in humans. For this reason, studies in animals are of particular importance. In experiments on rats, reproductive and developmental disorders proved to be the most sensitive indicators of excessive molybdenum intake, which led the two renowned scientific committees SCF (Scientific Committee on Food) and FNB (Food and Nutrition Board, Institute of Medicine) to agree on a NOAEL (No Observed Adverse Effect Level): No Observed Adverse Effect Level – the highest dose of a substance that has no detectable and measurable adverse effects even with continued intake) for molybdenum of 0.9 mg/kg body weight/day. In deriving the UL (English : Tolerable Upper Intake Level – safe maximum level of a micronutrient that does not cause adverse health effects in almost all individuals of all ages at daily, lifetime intakes from all sources) for molybdenum, there are discrepancies among the panels based on uncertainties due to lack of adequate human data. Based on the NOAEL for molybdenum, the SCF derived a UL of 0.01 mg Mo/kg body weight/day, corresponding to an adult intake of 600 µg Mo/day (6- to 12-fold the daily intake recommendation), using an uncertainty factor of 100 for humans.The FNB, on the other hand, set a UL for molybdenum of 2 mg/day for adults, based on the same NOAEL but using an uncertainty factor of 30. For children and adolescents, both scientific bodies derived their own Tolerable Upper Intake Levels, correspondingly lower to the UL for adults, because excessive molybdenum intakes in young animals had adverse effects on growth. The UK Expert Group on Vitamins and Minerals (EVM) has not set a UL for molybdenum due to insufficient data and considers that the maximum dietary intake of molybdenum observed in the UK of 230 µg/day does not pose a health risk. Permissible molybdenum compounds for use in dietary supplements and for fortification of dietary and conventional foods are sodium molybdate and ammonium molybdate (as anhydrate (without water molecules) and tetrahydrate (with 4 water molecules)). For dietary supplements, the addition of molybdenum should be limited to 80 µg per recommended daily intake and it should be clearly labeled that such products are unsuitable for children up to and including 10 years of age. However, due to existing uncertainties about current daily molybdenum intakes and possible exceedances of the UL, addition of molybdenum to both dietary supplements and dietary foods and conventional foods of general consumption should be avoided. The molybdenum concentration in plants is strongly dependent on the molybdenum content of the soil and on the soil or environmental conditions. A decrease in soil organic matter – humus depletion – and a low soil pH or a decrease in soil pH caused, for example, by acid rain, which leads to the conversion of MoO42- ions to sparingly soluble oxides, reduces molybdenum uptake by plants. Consequently, the molybdenum concentration of plant and animal foods can vary considerably, which is why widely different values are sometimes reported for molybdenum intake from food and drinking water in humans. Foods rich in molybdenum include cereal products, nuts, and legumes, such as beans, lentils, and peas. Foods of animal origin, fruits, and some vegetables, on the other hand, have low molybdenum contents [7, 10-12, 16, 25]. In regions, such as Linxian in northern China, where soils and foods are poor in molybdenum and the incidence (number of new cases) of gastroesophageal (“affecting the esophagus and stomach“) tumors is very high, enrichment of soils with ammonium molybdate could lead to an improvement in molybdenum supply and a reduction in tumor incidence in the population. The plant organism requires molybdenum to activate nitrate reductase, a molybdoenzyme that converts nitrate absorbed through the soil to nitrite, providing reduced, metabolizable (metabolizable) nitrogen in the form of ammonium (NH4+) for the synthesis of organic matter, such as amino acids. In the case of a molybdenum deficiency due to a reduced concentration in the soil, downregulation (downregulation) of nitrate reductase occurs, whereby nitrate in the plant is converted to nitrosamines, which enter the human organism through the consumption of plant foods and act as carcinogens (cancer-causing substances). Increased exposure to nitrosamines is one of the causes of the high incidence of gastroesophageal tumors in Linxian. By enriching soils with ammonium molybdate, nitrosamine formation in plants can be lowered, thus reducing the risk of tumor development. Whether oral intake of molybdenum supplements also reduces cancer risk is unclear. In the intervention study by Blot et al (1993), in which 29,584 Linxian subjects aged 40-69 years were followed over a 5-year period, substitution (dietary supplementation) of molybdenum (30 µg/day) and vitamin C (120 mg/day) did not decrease the incidence of gastroesophageal and other tumors.

Absorption

Molybdenum is absorbed in the small intestine, probably primarily in the duodenum (duodenum) and jejunum (jejunum), as molybdate (MoO42-). Little is known about the mechanism to date. It is assumed that molybdenum absorption is passive and that this process is not saturable. Depending on the source of the trace element, absorption rates range from about 35% to > 90% [4, 5, 11, 28-30].Molybdenum oxide and molybdates, such as calcium molybdate and thiomolybdate, are rapidly absorbed into enterocytes (cells of the small intestinal epithelium) with high efficiency (up to 80%). The absorption rate increases with decreasing supply and is reduced when supply exceeds demand. The more untreated or natural a food is, the better the bioavailability of molybdenum. Since the sulfate anion (SO42- ) has an electron configuration similar to that of the molybdate anion (MoO42-), the latter inhibits the transport of molybdate through both the apical (cell side facing the lumen) and basolateral (cell side facing the blood) enterocyte membranes. Similarly, copper ions decrease intestinal (gut-facing) molybdate absorption.

Transport and distribution in the body

Absorbed molybdate travels to the liver via the portal vein and from there to extrahepatic (“outside the liver”) tissues via the bloodstream. Human body molybdenum content of 5-10 mg (0.07-0.13 mg/kg body weight) is evenly distributed among organs and tissues, with the highest concentrations found in liver, kidney, adrenal gland, and bone (0.1-1 mg Mo/g wet weight). Molybdenum content in liver and kidney is unaffected by biological age and gender. Intracellularly (within cells), the binding of molybdenum occurs to the two sulfur (S) atoms of molybdopterin. By binding the molybdate-molybdopterin complex to molybdoenzymes, they are activated. While the molybdenum atom in the molybdopterin of mitochondrial sulfite oxidase has exclusively oxygen atoms bound, in the cofactor of cytosolic xanthine oxidase/dehydrogenase and aldehyde oxidase at the molybdenum atom one of the oxygen atoms is exchanged for sulfur (→ sulfurized molybdenum cofactor). Thus, two different molybdenum cofactors (desulfurized/sulfurized) exist in the human organism. Molybdenum occurs in the body mainly in bound form and only to a small extent as free molybdate. In whole blood (1-10 µg Mo/l), the trace element is predominantly found in erythrocytes (red blood cells), where it is bound to molybdoenzymes in complex with molybdopterin, among others. In serum (liquid, cell-free portion of blood minus clotting factors), which has a molybdenum concentration < 1µg/l, binding to alpha-2-macroglobulins (proteins of blood plasma), such as coeruloplasmin, is said to be present, which transports molybdenum from the liver to extrahepatic tissues. In the liver, molybdenum is found almost exclusively in complex with molybdopterin, with approximately 60% of these molybdenum cofactors bound to molybdoenzymes and circa 40% occurring as free cofactors. In bones and teeth, molybdenum is incorporated into apatite microcrystals, which explains its positive effect on bone and dental health. For example, the prevalence (disease frequency) of caries is very low in areas with fluorine-poor and at the same time molybdenum-rich soils, which is probably due to molybdenum-induced (triggered by molybdenum) increased intestinal absorption of fluoride and its increased incorporation into tooth enamel. In blood plasma, insoluble copper-molybdenum and/or sulfur-molybdenum complexes may form, affecting the kinetics (rate of biochemical processes) of the respective micronutrient. For example, an unphysiologically high copper or sulfur concentration in the body leads to increased binding of molybdenum, which impairs its transport to the tissues and its intracellular incorporation into molybdopterin. The result is a deficiency of molybdenum and a reduced activity of molybdoenzymes.Symptoms of molybdenum deficiency have so far only been observed in patients on permanent artificial nutrition, such as total parenteral nutrition (nutrition bypassing the gastrointestinal tract), with an excessively low molybdenum content and/or an excessive copper or sulfur concentration of the infusion solution, and in children with a rare inborn error of metabolism, such as molybdenum cofactor deficiency (disorders in the biosynthetic pathway of the organic component of molybdenum cofactor, molybdopterin, which limits the activity of molybdoenzymes) and isolated sulfite oxidase deficiency (oxidation from sulfite to sulfate is impaired, resulting in a deficiency of sulfate and an increase in sulfite concentration in all body fluids → sulfite toxicity), are observed. There is a close relationship between serum molybdenum concentration and liver functional status. For example, molybdenum concentrations can be found in a number of hepato-biliary (“affecting the liver and bile ducts”) diseases, such as hepatitis (inflammation of the liver), liver cirrhosis (end stage of chronic liver disease with disturbed tissue architecture, nodular changes and connective tissue proliferation), alcohol– and drug-induced liver damage as well as bile duct obstructions (caused by gallstones, tumors or inflammatory swellings with resulting bile backflow into the liver), detect elevated molybdenum levels in the blood serum. These are based either on decreased uptake of the trace element by the liver or on increased molybdenum release from damaged parenchymal cells.

Excretion

Absorbed molybdate is essentially excreted in the urine (10-16 µg/l) via the kidney. Elimination (excretion) via the bile with the feces (stool) plays a minor role. In breastfeeding women, about 10% of the intestinally absorbed molybdenum is additionally excreted with the milk (1-2 µg/l). Unabsorbed molybdenum leaves the body with the stool. Homeostatic regulation (self-regulation of equilibrium) of molybdenum occurs less by intestinal absorption than by adjustment of endogenous excretion (excretion). The kidney is of critical importance in this process, releasing molybdenum into the urine as a function of the amount of alimentary intake. Renal (affecting the kidney) molybdenum excretion is increased by increased dietary intake and by sulfate (SO42- ).