In this article we will discuss about:- 1. Introduction to Xenobiotics 2. Concept of Membranous Barrier 3. Responses to Xenobiotics.
Introduction to Xenobiotics:
Xenobiotics are the environmental chemicals. It is a term derived from the Greek word — xenon = a stranger + bios = life i.e., stranger to life.
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The salient xenobiotics of concern to human health and environment are listed in Table 14.1:
The metabolism of xenobiotics provides a basic knowledge to the understanding of pharmacology, toxicology, cancer research, drug addiction. All these areas involve exposure to xenobiotics.
Concept of Membranous Barrier:
When a xenobiotic (toxicant or drug) is administrated to an animal, its action is obstructed by certain barriers.
Chiefly these are:
(i) Blood-Brain Barrier
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(ii) Blood-Nerve Barrier
(iii) Placental Barrier
(iv) Blood-Renal Barrier
(v) Others.
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(i) Blood-Brain Barrier (BBB):
It protects the CNS from certain neurotoxins. This site is less permeable than other areas of the body. Blood-brain barrier is located at the capillary wall. Since the capillary endothelial cells are tightly joined, leaving few or no pores between these cells, the toxicant has to pass through the capillary endothelium itself.
Lack of vesicles in these cells further reduces their transportability. Finally, the protein concentration of the interstitial fluid in the brain is low, in contrast to that in other organs. Therefore, protein-binding does not serve as a mechanism for the transfer of toxicants from the blood to the brain.
Due to these reasons, the penetration of toxicants into the brain is dependent on their lipid solubility. An outstanding example is methyl mercury, which enters the brain readily and its main toxicity is observed on central nervous system. In contrast, inorganic mercury compounds, being insoluble in lipid, do not enter the brain readily nor adversely affect it. However, the kidney is not spared.
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The BBB is absent where the cells produce hormones or act as hormonal or chemoreceptors. Glutamate and a number of related compounds, such as aspartate, have been shown to affect certain areas in the brain unprotected by the BBB, e.g., the arcuata nucleus of the hypothalamus.
The BBB is effective in excluding many neurotoxins, such as diphtheria, staphylococus, and tetanus toxins. This is also true with doxorubicin, which affects the dorsal root ganglia but not the CNS. Mercury chloride has a small molecule but is hydrophilic and mainly in ionic forms. Its concentration in the brain is minimal and so are its CNS effects. The BBB is not completely developed at birth and, because of this reason, some toxicants prove to be more deleterious in newborns than in adults.
(ii) Blood-Nerve Barrier (BNB):
Peripheral nerves are covered by the connective tissue sheaths, the perineurium and epineurium interlaced with the endoneurium. The BNB is provided with the blood vessels in the endoneurium and supplemented by the lamellated cells of the perineurium sheath. It is not as effective as the BBB; therefore, the dorsal root ganglia are generally more susceptible to neurotoxins than the neurons in the CNS.
(iii) The Placental Barrier:
A number of toxicants may pass through the placenta by diffusion. The placental barrier differs anatomically as well as histologically among various animal species. There are six layer of cells between fetal and maternal blood in some species, whereas in others there is only one layer.
Furthermore, the number of layers may change as the gestation -progresses. Although the relationship of the number of layers of the placenta to its permeability needs quantitative determination, the placental barrier does impede the transfer of toxicants to the fetus, which is, therefore, protected to some extent.
However, the concentration of a toxicant such as methyl mercury may be higher in certain fetal organs, such as the brain, because of the less effective fetal blood-brain barrier. On the other hand, the foetal concentration of the food colouring amarnath is only 0.03- 0.06% of that of the mother. Placenta has capacity of metabolizing the xenobiotics (toxicant/ drugs) which may prevent the access of some toxicants to the fetus.
(iv) Blood-Renal Barrier:
Actually the kidney glomeruli act as membranous barrier for all protein bound xenobiotics. This barrier slows down the rate of transport of protein bound toxicants as well as lipophilic toxicants.
(v) Other Barriers:
Other barriers are also present in such organs as the eyes and testicles. In addition, the erythrocyte plays an interesting role in the distribution of certain toxicants. For example, its membrane acts as barrier against the penetration of inorganic mercury compounds but not to alkyl mercury. Furthermore, there is affinity of the erythrocyte cytoplasm for alkyl mercury compounds.
Because of these factors, the concentration of inorganic mercury compounds in the erythrocyte is only about half than that in the plasma, whereas that of methyl mercury in the erythrocyte is about ten times to that in the plasma. Also, lipid layer situated in between two protein layers in plasma membrane functions as barrier to the action of bio-activated toxicant.
Overall process of translocation of xenobiotics (toxicants) viz., Penetration, Biotransformation, Storage, Elimination (Excretion) and Deposition is shown in Fig. 14.3.
Responses to Xenobiotics:
When the xenobiotic is a drug, it may produce its active form or terminate its action if it is pharmacologically active in the body without prior metabolism. Here it is important to mention that drugs act through biochemical mechanisms.
Certain xenobiotics are very toxic (e.g., cyanide) and some xenobiotics are not so much toxic — even sufficient amounts of these are administered. The toxic effects of xenobiotics cover the wide spectrum.
Three general types of effects are mentioned here and shown in Fig. 14.4:
1. The first one is cell injury, which can result in cell death. The macromolecular targets include DNA, RNA and protein.
2. The reactive species of a xenobiotic may bind to a protein. The xenobiotic is said to act as a hapten. The resulting antibody can damage the cell by several immunologic mechanisms.
3. Reactions of activated species of chemical carcinogens with DNA are of great importance in chemical carcinogenesis. Some chemicals require activation by mono- oxygenases in the ER to become carcinogenic. The activities of the mono- oxygenases known as cytochrome P-450 species and of other xenobiotic- metabolizing enzymes present in the ER help to determine whether such compounds are carcinogenic or are detoxified. Other chemicals can react directly with DNA without undergoing intracellular chemical activation. Researches reveal that metabolites of certain xenobiotics can inhibit the activities of xenobiotic-metabolizing enzymes.
The enzymes exposide hydrolase can exert a protective effect against certain carcinogens. The action of certain monooxygenases on some procarcinogen substrates produces epoxides which are highly reactive and mutagenic or carcinogenic.
Epoxide hydrolase acts on epoxide forming dihydrodiols which are much less reactive:
