Liver metal transporters

N. Ballatori, Mechanisms of metal transport across liver cell plasma membranes. Drug Metab. Rev. 23 83-132, 1991. 

Pathway (IMP) uptake of iron. Blood 81, 517-521,1993 Wolf, G. and Wessling-Resnick, M., An integrin-mobilferrin iron transport pathway in intestine and hematopoietic cells, Nutr. Rev. 52, 387-389, 1994 Conrad, M.E. and Umbreit, J.N., Iron absorption and transport — an npdate, Amer. J. Hema-tol 64, 287-298, 2000 Umbreit, J.N., Conrad, M.E., Hainsworth, L.N., and Simovich, M., The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin. Am. J. Physiol. Gastrointest. Liver Physiol 282, G534-G539, 2002. 

Cells take up MT firom the circulation through a megalin/cubilin scavenger receptor pathway [26,27]. The internalized MT then releases cadmium in an endosomal/lysosomal compartment and divalent metal transporter 1 (DMTl) transports cadmium into the cytosol where it binds to extant MT and/or induces additional MT through the release of zinc from extant MT [28]. MT also is secreted from cells [29]. However, the pathway and mechanism of MT secretion remains elusive as in animals and man no pre-protein with an amino acid signature for export has been identified. Cd-MT may cross the plasma membrane of liver and other cells by fluid-phase exocytosis [30]. Extracellular MT is found under a variety of conditions including increasing cadmium loads [31]. 

The liver is a major metabolic organ for the in vivo handling of Cd (see the previous paragraph), but little is known about the metal transporters and molecular mechanisms involved in hepatic uptake of Cd. Work with isolated hepatocytes and human liver cell lines have demonstrated two possible routes of uptake One is for the free (ionic) form of Cd (Cd " ) and the other is for the complexed form of Cd " [233]. Cd " is most likely taken up by the same metal transporters that liver cells use to acquire physiologically essential metals, notably Fe ", Zn, Mn, and Cu ". Among those transporters is DMT-1, which is weakly expressed in liver [34,234]. Metal transporters of the Zrt-/Irt-like protein family, such as ZIPS and ZIP14 [35,234] are also expressed in liver. However, the localization and cellular orientation of these transporters in liver cells, has not been established. Many reports have postulated Cd " uptake by voltage-dependent calcium channels in hepatic cells, however, whereas whole liver expresses transcripts for L-type Ca channels, hepatocytes do not [235]. 

As lithium is an alkaline earth metal which readily exchanges with sodium and potassium, it is actively transported across cell membranes. The penetration of kidney cells is particularly rapid, while that of bone, liver and brain tissue is much slower. The plasma CSE ratio in man has been calculated to be between 2 1 and 3 1, which is similar to that found for the plasma red blood cell (RBC) ratio. This suggests that the plasma RBC ratio might be a useful index of the brain concentration and may be predictive of the onset of side effects, as these appear to correlate well with the intracellular concentration of the drug. 

A study in dogs indicates that absorption of inhaled metallic silver particles with a median aerodynamic diameter of approximately 0.5 pm is extensive, and is not dependent upon particle size (Phalen and Morrow 1973). Absorption was measured in one dog that remained anesthetized during the entire period between exposure and sacrifice. In this dog, 3.1% (0.8 pg) of the deposited material was dissolved, transported out of the lungs, and was found mostly in liver and blood 6 hours after exposure a 1 pg/cm /day absorption rate for metallic silver was estimated by the authors. Up to 90% of the deposited silver was estimated to be absorbed into the systemic circulation based on all experimental data. Clearance from the lung to the blood was triphasic, with half-lives of 1.7, 8.4, and 40 days. 

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