Manganese(2+)

Manganese mainly affects the nervous system and may cause behavioral changes and other nervous system effects, which include movements that may become slow and clumsy. This combination of symptoms when sufficiently severe is referred to as “manganism”. High levels of manganese may also cause damage to the reproductive system. (L228)

Manganese is a cellular toxicant that can impair transport systems, enzyme activities, and receptor functions. It primarily targets the central nervous system, particularily the globus pallidus of the basal ganglia. It is believed that the manganese ion, Mn(II), enhances the autoxidation or turnover of various intracellular catecholamines, leading to increased production of free radicals, reactive oxygen species, and other cytotoxic metabolites, along with a depletion of cellular antioxidant defense mechanisms, leading to oxidative damage and selective destruction of dopaminergic neurons. In addition to dopamine, manganese is thought to interact with other neurotransmitters, such as GABA and glutamate. Manganese overwhelms the manganese superoxide dismutase and produce oxidative damage. The neurotoxicity of Mn(II) has also been linked to its ability to substitute for Ca(II) under physiological conditions. It can enter mitochondria via the calcium uniporter and inhibit mitochondrial oxidative phosphorylation. It may also inhibit the efflux of Ca(II), which can result in a loss of mitochondrial membrane integrity. Mn(II) has been shown to inhibit mitochondrial aconitase activity to a significant level, altering amino acid metabolism and cellular iron homeostasis. (L228)

Mn²⁺ is an essential cofactor and activator for many enzymes that regulate biological functions and processes, such as oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. These enzymes include polysaccharide polymerase, liver arginase, cholinesterase, pyruvate carboxylase, and Mn superoxide dismutase (MnSOD). These enzymes regulate immune function, metabolism, growth potential, hemostasis, mitochondrial homeostasis and antioxidant function, and neuronal function.

Mn²⁺ is oxidized to Mn³⁺ by liver and plasma ceruloplasmin.

Manganese is mainly absorbed via ingestion, but can also be inhaled. It binds to alpha-2-macroglobulin, albumin, or transferrin in the plasma and is distributed to the brain and all other mammalian tissues, though it tends to accumulate more in the liver, pancreas, and kidney. Manganese exists in a number of oxidation states and is believed to undergo changes in oxidation state within the body. Manganese oxidation state can influence tissue toxicokinetic behavior, and possibly toxicity. Manganese is excreted primarily in the faeces. (L228)

When orally administered, manganese (Mn) is reported to be readily absorbed through the intestinal tract: about 3–5% of dietary Mn is absorbed as Mn2+ and Mn4+. Under conditions of minimal intake, 20 mcg Mn/day is retained following intravenous administration. Assays for manganese in whole blood result in concentrations ranging from six to 12 mcg/Mn/L.

Excretion of manganese occurs mainly through the bile, but in the event of an obstruction, ancillary excretion routes include pancreatic juice or return into the lumen of the duodenum, jejunum, or ileum. Urinary excretion of manganese is negligible.