Manganese1



Manganese1


Alan L. Buchman





HISTORY, CHEMISTRY, AND BIOCHEMISTRY

Manganese (Mn) was first isolated as a free metal in 1774 following the reduction of its dioxide with carbon. It was first found as a constituent of animal tissues in 1913, although a state of deficiency (in animals) was not described until 1931 (1, 2, 3). Mn is a hard, brittle metal. Its oxidation state ranges between -3 and +7, although the most stable valence is +2 and the most abundant is 4+. Mn2+, the only form absorbed by humans, is oxidized to Mn3+, the oxidative state, over time in plasma. The human body contains approximately 10 to 20 mg of Mn, with 25% to 40% present in bone and 5 to 8 mg turned over on a daily basis. The biologic half-life of Mn ranges from approximately 12 to 40 days (4).


Associated Enzymes

Mn is essential as a cofactor for the metalloenzymes superoxide dismutase (SOD), xanthine oxidase, arginase, galactosyltransferase, and pyruvate carboxylase (5). It functions as a constituent of these metalloenzymes or as an enzyme activator. SOD activity is depressed in Mn-deficient animals (6). SOD protects the cell against antioxidant processes, including injury associated with radiation, chemicals, and ultraviolet light. Mn binding to arginase has significant importance in nitrogen metabolism through the ornithine cycle (7). It hydrolyzes L-arginine to urea and L-ornithine. Decreased arginase results in increased plasma ammonia in rats (8). Pyruvate carboxylase is involved in gluconeogenesis, but its activity appears minimally affected by Mn deficiency, except in newborns (6, 9). Mn also activates numerous enzymes including various decarboxylases, glutamine synthetase, hydrolases, kinases, and transferases such as glycosyltransferases, the last of which are involved in polysaccharide biosynthesis (10). Depressed galactosyltransferase activity may account for the connective tissue defects observed in Mn-deficient animals (11). Activation of these enzymes by Mn probably involves Mn binding to the protein that induces a conformational change or binding to a substrate such as adenosine triphosphate (ATP). Mn is not essential to most of these enzyme systems, which can also be activated by other metals, except for glycosyltransferases. Therefore, at least in nonprimate animals, Mn deficiency can result in defective cartilage formation in animals.


DIETARY CONSIDERATIONS

Dietary Mn is found primarily in whole grain cereals, legumes, nuts, coffee, and tea. A 1982 study of 10,000 French households found that the average daily Mn intake was 2 mg/day based on purchases of food designed to total 2000 kcal /day (8360 kJ/day) (12). Other dietary surveys in the United States, Canada, and New Zealand have shown intake to range between 2.0 and 4.7 mg/day, with vegetarians having significantly greater intake (13). Daily food intake ranges between 2 and 6 mg/day and up to 11 mg/day in vegetarian diets (13).

Orally consumed adult nutritional formulas have a range of Mn content from 0.7 to 1.2 mg/237 mL (14, 15). The actual concentration may differ from that shown on the formula label (16). In a study of 116 milk samples from 24 lactating women in Champaign-Urbana, Illinois, the concentration of Mn was found to range between 1.9 and 27.5 µg/L (0.03 and 0.50 µmol/L), with a mean value of 4.9 ± 3.9 µg/L (0.09 ± 0.07 µmol/L); infants consumed approximately 0.4 µg/kg/day (17). Bovine-based infant formula contains 30 to 75 µg/L (0.54 to 1.35 µmol/L),
and soy-based formula contains approximately 100 to 300 µg/L of Mn (1.8 to 5.4 µmol/L) (18). Cow’s milk has significantly more Mn than does human milk (19). For adults, most studies have shown that an intake of 2 to 5 mg/day is sufficient to remain in positive Mn balance, although individual variation is significant. For example, men absorb less Mn, but they retain it longer than do women (20).

The dietary reference intakes of the Food and Nutrition Board, Institute of Medicine for Mn are given in Table 15.1. From the criteria list, it is apparent that none of the values are based on quantitative biochemical data. Because insufficient data were available for a recommended dietary allowance to be formulated, the adequate intake (AI) value of Mn is indicated. For infants, the AI reflects the mean intake of Mn from breast milk. For adults, the AI was set based on median intakes reported in the US Food and Drug Administration Total Diet Study. Although no documented need exists for dietary Mn supplementation, absorption of Mn supplements is substantially greater in the fasting state (15). The tolerable upper intake level (UL) is described later in this chapter. Toxicity from usual dietary intake is unusual, given that only approximately 5% of dietary Mn is absorbed (16, 17).


Parenteral Nutrition

For patients who require parenteral nutrition (PN), the American Society for Parenteral and Enteral Nutrition recommended 0.06 to 0.10 mg/day in adults and 0.001 to 0.150 mg/kg for children, depending on age (18). Contamination in PN components is low (<3 to 20 µg/day); therefore, nearly all Mn in PN is derived from the addition of a multitrace metal complex (19, 20, 21, 22, 23, 24). At the low end of probable requirements, however, such contamination could supply up to one third of the daily need. Data on various concentrations of Mn in patients who received long-term PN indicated that blood concentrations could be maintained at adequate levels at 60 to 120 µg/day (1.5 to 3.0 µg/kg) (25). Human deficiency, even in the absence of Mn supplementation, has not clearly been described in patients receiving PN, however, and supplementation may not be required. Mn supplementation should cease in the presence of biliary obstruction or cholestasis jaundice, because of decreased Mn excretion with subsequent accumulation in tissues (see the later discussion of toxicity).


Nutrient-Nutrient Interactions

The addition of large doses of Mn (four to eight times the AI) leads to a decrease in iron absorption by approximately one third (26). Mn supplementation leads to decreased iron absorption in iron-deficient animals, although this effect has not been demonstrated in humans (27). Investigators have also suggested that Mn absorption is enhanced in iron sufficiency and is decreased in iron deficiency (28). Therefore, Mn may possibly be recognized by the intestinal iron transport mechanism, and factors that regulate iron absorption may also then regulate Mn absorption. In no other known situations does Mn ingestion have any effect on other nutrient, metal, or medication absorption. Adding calcium (Ca) to human milk and increasing dietary phytate have been shown to reduce Mn absorption (29, 30).

Because of biliary excretion (31), balance studies are not particularly useful in the determination of daily requirements. Therefore, most estimates of absorption are based on whole body retention after 10 to 30 days of using 54Mn.








TABLE 15.1 CRITERIA AND DIETARY REFERENCE INTAKE VALUES FOR MANGANESE BY LIFE STAGE GROUP


































































































AI (mg/d)a


LIFE STAGE GROUP


CRITERION


MALE


FEMALE



0-6 mo


Average manganese intake from human milk


0.003


0.003



7-12 mo


Extrapolation from adult AI


0.6


0.6



1-3 y


Median manganese intake from FDA Total Diet Study


1.2


1.2



4-8 y


Median manganese intake from FDA Total Diet Study


1.5


1.5



9-13 y


Median manganese intake from FDA Total Diet Study


1.9


1.6



14-18 y


Median manganese intake from FDA Total Diet Study


2.2


1.6



≥19 y


Median manganese intake from FDA Total Diet Study


2.3


1.8


Pregnancy






14-18 y


Extrapolation of adolescent female AI based on body weight



2.0



19-50 y


Extrapolation of adult female AI based on body weight



2.0


Lactation






14-18 y


Median manganese intake from FDA Total Diet Study



2.6



19-50 y


Median manganese intake from FDA Total Diet Study



2.6


FDA, Food and Drug Administration.


a AI, adequate intake. The observed average or experimentally determined intake by a defined population or subgroup that appears to sustain a defined nutritional status, such as growth rate, normal circulating nutrient values, or other functional indicators of health. The AI is used if sufficient scientific evidence is not available to derive an estimated average requirement (EAR). For healthy infants receiving human milk, the AI is the mean intake. The AI is not equivalent to a recommended dietary allowance.


Reproduced with permission from Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2001.




ABSORPTION, TRANSPORT, AND EXCRETION

Dietary Mn is absorbed by a diffusion mechanism and a transport mechanism that are rapidly saturable (32, 33). Approximately 6% to 16% of dietary Mn is absorbed (mean, 9%), with a retention half-life of 8 to 33 days (19, 34, 35). Mena (36) found that retention was 15.4% in premature infants at 10 days, but only 8.0% in term newborns and 1.0% to 3.0% in adults. The better absorption from human milk than from bovine milk or soy-based formula may be related to the decreased concentration of Mn in human milk or the increased binding of Mn in human milk to lactoferrin, the increased Ca content of bovine milk, and, for soy-based formula, the relatively large amounts of phytic acid (37, 38). No other dietary factors are known to affect Mn absorption, including ascorbic acid.

Homeostatic mechanisms control intestinal absorption; lower amounts are absorbed during periods of significant exposure (39). The cellular mechanisms that govern absorption and the mechanism that controls absorption are unknown, however. Absorption is increased in patients with hemochromatosis (34), as well as in patients with iron deficiency (36). Mn absorption is decreased in the presence of a large Ca load (40). Mn sulfate is the most soluble salt and is therefore the form found in most nutritional supplements (41). After absorption into the portal circulation, Mn may remain either free or bound preferably to transferrin (42), but also to α2-macroglobulin (43, 44) and albumin (45) to a lesser extent, all three of which are rapidly taken up by the liver.

In serum, Mn appears to be bound primarily to transferrin (44) and an α2-macroglobulin (46), although binding to transferrin, at least, does not appear to be essential for Mn uptake by extrahepatic tissues (47). The divalent form of Mn is firmly bound within the erythrocyte. The mechanism by which Mn is transported to and taken up by extrahepatic tissues has not yet been clearly elucidated, but it appears to involve internalization within endosomal vesicles as well as voltage-regulated Ca channels (48). Mn crosses the blood-brain barrier by carriermediated transport, although the specific carrier has not been elucidated (49, 50). Some evidence suggests that the primary carrier protein is divalent metal transport-1 (DMT1) (51). Conflicting data suggest otherwise, however (52). Crossgrove and Yokel (53) suggested that store-operated Ca channels are largely responsible for the transport of Mn across the blood-brain barrier. Over time, Mn2+ is oxidized to Mn3+ in plasma (54, 55) possibly by ceruloplasmin (46), which is also bound to transferrin (46). Transferrin may be the moiety that accumulates in tissues (55). When Mn is oxidized, it becomes more tightly bound to transferrin (46). Newer data suggest a possible role of the zinc transporters, ZIP8 (SLC39a8) and ZIP14 (SLC39a14) in manganese uptake (56, 57) (see also Chapter 11: Zinc). These transport processes and the potential competition of Mn ions with other divalent and trivalent metal ions are illustrated schematically in Figure 15.1.

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Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Manganese1
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