Xenobiotics usually pass through a number of cells, such as the stratified epithelium of the skin, the thin cell layers of the lungs or G.I.T., the capillary endothelium, and the cells of target organ or tissue. The cell membrane (plasma membrane) surrounding all these cells are remarkably similar. It is approximately 100 A0 thick with pores of size ranging from 4 to 40 A0. The lipid layer of the plasma membrane is permeable to and readily penetrated by lipid soluble substances.
In order to enter the animal and reach some target organ, any xenobiotic (toxicant) must penetrate one or more living membrane(s). The membranes form barriers through which toxicants have to cross to exert their deleterious effects at one site or several sites in the body.
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Exceptions are caustic and corrosive agents (acids, bases, salts, oxidizers), which act topically. A toxicant absorbed into the blood stream through any barrier is distributed, at least to some extent, throughout the body, including the site where it produces damage. This site is often called the target organ or target tissue.
It is to be emphasized here that a xenobiotic may have one or several target organs, and, in turn, several xenobiotics may have same target organ. For example, benzene affects the hematopoietic system and CCl4 injures the liver. Lead and mercury both damage the CNS, the kidneys, and the hematopoeitic system.
Toxic agents in different ways may modify the permeability of plasma membrane. For instance, size, shape, degree of ionization, and lipid solubility of ionized and non-ionized forms of a xenobiotic (toxicant) are its important physio-chemical properties that influence its passage across the plasma membrane.
A toxicant may pass through plasma membrane by one of the two general processes:
1. Passive transport (diffusion according to Fick’s law) in which the cell expends no energy, and
2. Specialized transport, in which the cell provides energy to translocate the xenobiotic (toxicant) across its membrane.
1. Passive Transport:
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Simple Diffusion:
Most xenobiotics cross cell membranes by simple diffusion. Small hydrophilic molecules (up to a molecular weight of about 600) presumably permeate membranes through aqueous pores, whereas hydrophobic molecules diffuse across the lipid domains of membranes. The smaller a hydrophilic molecule is, the more readily it traverses membranes by simple diffusion through aqueous pores. Consequently, ethanol is absorbed rapidly from the stomach and intestine and is distributed equally rapidly throughout the body by simple diffusion from blood into all tissues.
The rate of passage is related directly to the concentration gradient across the membrane and to the lipid solubility. For example, mannitol is hardly absorbed (< 2%); acetylsalicylic acid is fairly well absorbed (21%); and the thiopental is even more readily absorbed (67%).
Many toxicants are ionizable. The ionized form is often unable to penetrate the cell membrane because of its low lipid solubility.
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The degree of ionization of a chemical depends on its pKa and on the pH of the solution. The relationship between pKa and pH is derived by the Henderson-Hasselbalch equation-
Some examples are:
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For Weak Acids:
For Weak Bases:
Filtration:
The membranes of the capillaries and the glomeruli have relatively large pores (about 40 A0) and allow molecules smaller than albumin (mol. wt. 60,000) to pass through. Bulk flow of water through these pores results from hydrostatic and/or osmotic pressure and can act as carrier of toxicants. The pores in most cells, however, are relatively small (about 4 A0) and allow chemicals only up to a mol. wt. of 100 – 200 to pass through.
Chemical of larger molecules, therefore, can filter into and out of the capillaries. They can, therefore, establish equilibrium between the concentrations in the plasma and in the extracellular fluid, but they cannot do so by filtration between the extracellular and intracellular fluids.
2. Specialized Transport:
There are numerous compounds whose movements across membranes cannot be explained by simple diffusion or filtration. Some compounds are too large to pass through aqueous pores or too insoluble in lipid domains of membranes. Nevertheless, they often are transported very rapidly across membranes, even against concentration gradients. To explain these phenomena, the existence of specialized transport systems has been postulated. These systems are responsible for the transport across cell membranes of many nutrients, such as sugars, amino acids, nucleic acids, and also that of some foreign compounds.
Active Transport:
The following properties denote an active transport system:
i. Chemicals are moved against electrochemical or concentration gradients.
ii. The transport system is saturated at high substrate concentrations and thus exhibits a transport maximum (Tm).
iii. The transport system is selective for certain structural features of chemicals and has the potential for competitive inhibition between compounds that are transported by the same transporter, and
iv. The system requires expenditure of energy so that metabolic inhibitors block the transport process.
Substances actively transported across plasma membranes presumably form a complex with membrane-bound macromolecular carrier on one side of the membrane. The complex subsequently traverses to the other side of the membrane, where the substance is released. Afterward, the carrier returns to the original surface to repeat the transport cycle.
Active transport is especially important in regard to eliminating xenobiotics from an animal. The central nervous system (CNS) has two transport systems at the choroid plexus to transport compounds out of the cerebrospinal fluid (CSF) — one for organic acids and one for organic bases. The kidney also has two active transport systems, whereas the liver has at least four, two of which transport organic acids, one organic base and one neutral organic compound.
Facilitated Diffusion:
Facilitated diffusion applies to carrier-mediated transport that exhibits the properties of active transport, except that the substrate is not moved against an electrochemical or concentration gradient and the transport process does not require the input of energy; that is, metabolic poisons do not interfere with this transport. The transport of glucose from the gastrointestinal tract (GIT) across the basolateral membrane of the intestinal epithelium, from plasma into red blood cells and from blood into the CNS, occurs by facilitated diffusion.
Additional Transport Processes:
Other forms of specialized transport have been proposed, but their overall importance is not as well-established as that of active transport and facilitated diffusion. Phagocytosis (cell eating) and pinocytosis (cell drinking) are proposed mechanisms for cell membranes flowing around and engulfing particles. This type of transfer has been shown to be important for the removal of particulate matter from the alveoli by phagocytes and from blood by the reticuloendothelial system of the liver and spleen.