Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese.
Chronic exposure to the divalent heavy metals, such as iron, lead, manganese (Mn), and chromium, has been linked to the development of severe, often irreversible neurological disorders and increased vulnerability to developing Parkinson's disease. Although the mechanisms by which these metals elicit or facilitate neuronal cell death are not well defined, neurotoxicity is limited by the extent to which they are transported across the blood-brain barrier and their subsequent uptake within targeted neurons. Once inside the neuron, these heavy metals provoke a series of biochemical and molecular events leading to cell death induced by either apoptosis and/or necrosis. The toxicological properties of Mn have been studied extensively in recent years because of the potential health risk created by increased atmospheric levels owing to the impending use of the gas additive methylcyclopentadienyl manganese tricarbonyl. Individuals exposed to high environmental levels of Mn, which include miners, welders, and those living near ferroalloy processing plants, display a syndrome known as manganism, best characterized by debilitating symptoms resembling those of Parkinson's disease. Mn disposition in vivo is influenced by dietary iron intake and stores within the body since the two metals compete for the same binding protein in serum (transferrin) and subsequent transport systems (divalent metal transporter, DMT1). There appear to be two distinct carrier-mediated transport systems for Mn and ferrous ion: a transferrin-dependent and a transferrin-independent pathway, both of which utilize DMT1 as the transport protein. Accordingly, this commentary focuses on the biochemical and molecular processes responsible for the cytotoxic actions of Mn and the role that cellular transport plays in mediating the physiological as well as the toxicological actions of this metal.
Roth
Jerome A
JA
Department of Pharmacology and Toxicology, 102 Farber Hall, University at Buffalo, Buffalo, NY 14214, USA. jaroth@buffalo.edu
Garrick
Michael D
MD
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D027682:Cation Transport Proteins / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D033862:Iron-Binding Proteins / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology*; D020149:Manganese Poisoning / Q000378:metabolism*; D012129:Respiratory Function Tests; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D007501:Iron; D033862:Iron-Binding Proteins; D008345:Manganese; D000099236:Solute Carrier Family 11, Member 2