Oral Bioavailability - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 294

Transporter 4 Precursor, ZIP4 (not presented in Fig. 7.5 ). On ingestion of exces-
sive doses of mineral salts, the gradient between the intestinal lumen and plasma
or cell will be so large that it allows for passive diffusion (proportional to the con-
centration between the two compartments) to occur. In this instance, the process of
active transport from the lumen to systemic circulation is decreased, because the
absorption of mineral salts would be too high, and there is an increase in the excre-
tion of the mineral salts e.g. through sweating in order to protect the organism from
poisoning.
Divalent cations, such as calcium, cadmium, copper, magnesium, manganese,
iron and zinc, exhibit similar common behaviour under the acidic pH conditions in
the very upper intestine ( proximal duodenum ):

• ionisation and solubilisation in the intestinal fluids;

• binding to transmembranar proteins;

• active process (energy consumption) during apical crossing;

• intracellular release as ions and chelation.

For example, iron is absorbed in the proximal duodenum. In order for the
absorption process to be efficient, an acidic environment is required (where the
solubilisation and ionisation processes occur), however, these conditions may be
hindered by the ingestion of antacids etc., that interfere with gastric acid secretion.
Ferrireductase reduces ferric to ferrous iron in the duodenal lumen and after binding
to the transmembranar protein DMT-1, the iron is cotransported with a proton into
the absorbtive intestinal cells. The transmembranar protein DMT-1 is not iron spe-
cific, it is a transporter of many divalent metal ions. Once inside the intestinal cell,
the absorbed iron may follow one of two major pathways, which is dependant on
the dietary status of the host and the iron loading already present in the cell. For iron
abundant states, the iron within the cell is trapped by incorporation into ferritin. This
iron is not transported to the blood and the iron is lost when the cell dies. Whereas
under conditions where there is a paucity of iron; the absorbed iron is exported from
the cell via the transporter ferroportin, which is found in the basolateral membrane,
and transported through the body after binding to the iron-carrier transferrin (i.e.
intracellular release and chelation).
During the protein binding steps in the active transport process cations may inter-
act, as antagonists (i.e. oppose the action of additional cations or bind to the receptor
without producing a response). Thus the absorption of specific bioaccessible cations
to the binding/carrying proteins may be affected by the presence of other cations in
the target organ and competition with other bioaccessible contaminants. For exam-
ple, this regulation means that cadmium absorption can be affected not only by a
competition with other ions to bind to the ligand site, but also by the iron status of
the receptor.
For some metals bound to amino-acids in soil, absorption can occur via amino
acid carriers. In the case of copper, the amino acid carrier is histidine, whereas for
selenium, methionine complexes are formed. After their translocation to plasma,
metals can be bound to specific or non-specific carriers. Specific carriers include