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.

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).

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.