Oral Bioavailability - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 295

transferrin (a blood plasma protein for iron delivery), transcobalamin (a group
of proteins (of intestinal cells) that bind to cyanocobalamin (vitamin B12) and
transport it to other tissues) and nickeloplasmin (a nickel containing protein), the
non-specific class of carriers includes albumin and amino-acids.
When considering the organic contaminants of major concern, i.e. dioxins,
polychlorobiphenyls (PCBs) and polyaromatic hydrocarbons (PAHs), absorption
through the intestinal epithelium is commonly described by a passive diffusion
model (Cavret and Feidt 2005 ). However, because there is a large variation in
behaviour amongst the organic contaminants of interest, intestinal absorption of
organic contaminants will not be covered in great detail in this chapter. In the pas-
sive diffusion model, the diffusion flow is proportional to the concentration gradient
between the luminal and plasmatic compartments, according to their lipid contents.
Most organic contaminants of interest are not readily soluble in aqueous digestive
fluid, because of their hydrophobicity, and are conveyed by micellar solutions of
conjugated bile salts. Bile acids are facial amphipathic molecules, i.e., they con-
tain both hydrophobic (lipid soluble) and polar (hydrophilic) faces. Therefore, bile
salts act as lipid carriers and are able to solubilise many organic contaminants by
forming micelles, aggregates of lipids such as fatty acids, cholesterol and mono-
glycerides, which remain suspended in water and can reach the epithelium. Once
the organic contaminants reach the double-layered membrane, their hydrophobicity
favours their uptake across the epithelium (Fig. 7.3 ).

7.1.1.3 Metabolisation in the Liver

After absorption, contaminants migrate through the portal vein into the liver, in
which they may undergo biotransformation . The most common transformation
mechanisms are hydroxylation for lipophilic organic contaminants (PAHs, PCBs,
dioxins), whereas the cationic metals are bound by proteins (Webb 1986 ). Arsenic,
mostly under anionic form, may undergo methylation (Tseng 2009 ). Once absorbed
and passed through the portal vein, contaminants may be:

• sequestrated within the liver (metals bound to proteins or PCDF bound to

cytochrome P450);

• excreted in bile, either unaltered or in a metabolised/bound form; or

•

released into the systemic circulation.

These processes are complex, because of the enzymes involved in the biotrans-
formation process and the inducible production of binding proteins. The amount of
contaminant metabolisation, via bile excretion, is dose dependant. At a low dose,
the amount of activity will not be sufficiently efficient; however, continual expo-
sure increases enzymatic activity due to DNA regulation, increasing the metabolism
capacity followed by the rate of metabolism. The metabolism of a particular sub-
stance can be affected by both interspecies and inter-individual differences, thus
contaminants that may be benign to humans may be highly toxic to other species
and vice versa (Fowles et al. 2005 ).