Translocation of Xenobiotics
The chemicals penetrate into the various fluid compartments after absorption into the blood stream, which are plasma, interstitial fluid, trans-cellular fluid, and cellular fluids. Non-ionised lipid soluble fractions penetrate most readily. Generally, equilibrium in most tissues takes place rapidly. However, in bone and adipose tissues there is a poor blood supply therefore, relatively longer time is required to achieve equilibrium in them. Moreover, some chemicals may get deposited in various areas as a result of binding or due to their affinity for fat. The accumulation may serve as a storage depot for the chemical.
The complex membranous system of the organism’s body is effectively involved in the distribution of chemicals. There exist several types of such barriers that affect the distribution of toxic agents. These tissue permeability barriers are discussed here below.
Biological complexity and specialization depend on the existence of permeability barriers across which concentration gradients can be established and maintained. Thus in most tissues including testes, cellular organisation precludes continuous membrane barriers and raises the possibility of diffusion around membranes through extracellular spaces. In endothelia and epithelia, the extracellular diffusion occurs through narrow intercellular clefts between membranes of adjacent cells. This specialised intercellular cleft is known as tight junction or zona occludents.
In permeability barriers, the effective tight junction occurs at the level of capillary endothelium. E.g. brain, placenta, and thymus barriers. These barriers restrict the exchange of certain molecules between the blood inside capillaries and the tissue fluid outside. These barriers are called blood organ barriers. In blood- bile barrier, the blood has direct access to the membranes of the hepatocytes. Tight junctions formed by the adjacent hepatocytes constitute the physical barrier immediately interposed between blood and bile. Some blood organ barriers do not directly involve the blood. For instance, in blood- urine barrier tight junction occurs near the luminal surface of the bladder epithelial cells and in the blood-testes barrier within the seminiferous tubules. Thus blood-testes barrier resembles the blood-urine barrier more than the blood-brain barrier with which it is often compared.
The blood-brain barrier is located between the plasma and extracellular space of the brain either at the capillary endothelial cells or at the glial field that surrounds the brain capillaries. The blood-cerebrospinal fluid barrier is located at choroid plexus. These barriers are not absolute barriers to the passage of chemical into the central nervous system but rather represent a site that is less permeable than most other areas of the body. The passage of chemicals into brain, in general, follows the same principle as for transfer across other cells in the body. The chemicals which are not bound to plasma proteins are free to enter the brain. If a chemical is ionized it will not enter the brain, whereas non-ionised ones will enter the brain readily at a rate proportion to its lipid water coefficient. The route for exit of chemicals from the cerebrospinal fluid differs from the route of entrance since the chemicals leave the cerebrospinal fluid by bulk fluid flow through the arachnoid villi.
Many xenobiotics may cross the placenta and exert their toxic effect on fetus. They may induce foetal deaths and even congenital anomalies. The passage of chemicals across the placental membranes occurs primarily by simple diffusion: carrier-mediated transport generally restricted to endogenous substrates. Here again the same factors, especially lipid water partition coefficient are chief determinants in the placental transfer. However, the concentration of chemicals in various tissues of the fetus will be determined by the ability of the individual tissue to concentrate the chemicals which may be dependent upon plasma-protein concentration and binding affinity for various chemicals.
Like other barriers, blood-testes barrier is specific consequence of intercellular tight junctions interposed either directly or indirectly between the blood and another distinctive fluid compartment. It occurs between sertoli cells in the seminiferous epithelium. The tight junction, which is part of elaborate sertoli cell junctional complex, consists of extraordinary number of lines of membrane fusion in parallel way. This barrier has an important protective role in safeguarding the germ line from noxious influences originating both from within and outside. The barriers also help in shielding meiotic cells from environmental mutagens and in prevention of autoimmune orchitis.
This barrier is in fact involved in general renal excretion of undesirable xenobiotics and their metabolites from the body. Toxic compounds can be excreted from the plasma by passive diffusion through the renal tubules into the urine. Like other biological membranes, the tubular epithelium, particularly in the distal tubule, behaves as a lipoprotein barrier allowing the transfer of lipid- soluble non-ionized molecules. Lipid-soluble compounds present in the glomerular filtrate in the non-ionized form are therefore reabsorbed into the blood stream whereas the compounds of low lipid-solubility are only partially reabsorbed.
Like renal excretion, the liver is the second important route of excretion of toxic chemicals and other wastes from the body. Besides working as a route of general excretion, liver also provides an effective barrier to the passage of toxic chemicals. The blood from gastrointestinal tract passes through liver before reaching the general systemic circulation. Liver removes the compounds from blood and prevents their distribution to the body. Compounds may be excreted directly into the bile without re-entering the blood stream to be excreted by liver cells into bile and thus passes into small intestine. If the properties of the chemical or their metabolites are favourable for the intestinal reabsorption, a cycle may result (enterohepatic cycle), in which biliary secretion and intestinal reabsorption continue until renal excretion finally eliminates the compounds from the body.
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