Page 167 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

134 SECTION | I General

VetBooks.ir environment by crossing cellular barriers. The primary through transmembrane transporter proteins. Factors
that determine a compound’s rate and extent of distribu-
routes of exposure for toxic substances are oral, respiratory,
tion therefore include molecular size, lipophilicity,
and dermal.
The gastrointestinal, respiratory, and dermal systems plasma protein binding and the ability to interact with
are lined with epithelia that present significant barriers to transmembrane transporter proteins. Uneven distribution
the entry of foreign substances due to tight junctions through the body may occur due to affinity for specific
between their cells, or continuous lipid layers in the case environments such as fat for highly lipophilic com-
of skin. The membranes of cells that form viable epithe- pounds or bone for compounds that bind to Ca 21 .This
lial barriers are traversed by transporter proteins that can lead to extremely low concentrations in the blood
either actively exclude xenobiotics, or facilitate the move- plasma and accumulation with prolonged storage of the
ment of specific substrates across the barrier. The onset, compound at the depot sites.
duration, and intensity of a substance’s toxic effects are
therefore dependent on the toxicant’s ability to permeate
lipid cell membranes directly, and its interactions with Biotransformation
transporter proteins. Dermal penetration is unique in the
sense that the outer epithelial cellular layers (corneocytes) Biotransformation is a key body defense mechanism
are nonviable and do not contain transporter proteins. whereby chemical reactions transform xenobiotic com-
Absorption, in this case, is therefore dependent on the pounds in the body. The major transformation reactions
ability of toxicants to penetrate the intercellular lipid for xenobiotics are divided into two phases. Phase I reac-
matrix found between corneocytes. There are several tions (oxidation, reduction, hydrolysis, and acetylation)
factors that may influence the permeability of epithelial modify the compound’s structure by adding a functional
barriers to specific xenobiotics, including the physico- group. This allows the substance to interact with Phase II
chemical properties of the substance, blood supply at the enzymes, which conjugates it with a water-soluble molecule
site of exposure, and the concentration of the substance at such as sulfate, glucuronide, glutathione, and amino acid.
the site of contact. A specific compound may be catego- The water solubility of a compound is typically increased
rized as relatively nontoxic by one route and highly by this process, and it is an important step towards the
toxic via another due to differences in absorption from excretion of lipid soluble toxicants. Water-soluble com-
these sites. pounds that are small enough to pass through the renal glo-
merulus can usually be excreted relatively rapidly through
the urine without biotransformation. Biotransformed toxi-
Distribution
cants will often have reduced toxicity compared to the par-
Distribution is the process whereby toxicants move ent compounds. In some cases, however, biotransformation
throughout the body and reach their site of action. increases toxicity. Biotransformation enzymes have broad
Once absorbed, a toxicant typically enters the intersti- substrate specificity. They are, therefore, able to transform
tial fluid at the site of absorption and then passes into a wide range of substrates.
the tissue cells or enters the blood and/or lymph. Blood
is moved rapidly through the body by the cardiovascu-
lar circulatory system and this process constitutes
Excretion
the major mechanism whereby absorbed chemicals are
distributed to the various organs and tissues of the One of the primary mechanisms of protecting the body
body. from the toxic effects of toxicants is the elimination of
To be distributed through the body by the cardiovas- these compounds from the body. Compounds that are rap-
cular system, a toxic chemical must first cross the idly eliminated are less likely to accumulate in tissues and
capillary endothelium, and then diffuse through the damage critical cells. Although the terms elimination and
interstitial fluid and penetrate the cells of the target excretion are sometimes used synonymously, the former
organ. The entrance of xenobiotics to some tissues is term encompasses all the processes that decrease the
restricted by special barriers (e.g., blood brain barrier, amount of parent compound in the body, including bio-
blood testes barrier, and blood placenta barrier) that transformation. Excretion is the term used specifically to
form continuous cellular layers with tight junctions that refer to the processes by which toxic compounds leave
prevent movement of toxicants into tissues by passive the body through excretory organs. The main routes of
diffusion through intercellular spaces. To gain entry into elimination are urine, feces, and exhaled air. Except for
these protected tissues, toxicants must pass through lipid the lung, water-soluble substances are more readily
cell membranes, either by penetrating the lipid mem- excreted because they are not readily reabsorbed through
branes directly, or by active or facilitated transport cellular barriers in the excretory organs.