The following points highlight the thirteen main principal storage sites for xenobiotics in the living system. The storage sites are: 1. Plasma Proteins 2. Body Fat 3. Liver 4. Kidney 5. Bone 6. Brain and Nervous Tissues 7. Erythrocytes 8. Gonads 9. Respiratory Tract 10. G.I.T. 11. Gall Bladder 12. Spleen 13. Fetus.
1. Plasma Proteins as Storage Depot:
Several plasma proteins — for example albumin, transferring, ceruloplasmin, α & β lipoprotein etc. — may bind some xenobiotics (toxicants). The extent of plasma protein binding varies considerably among xenobiotics. For example, antipyrine is not bound. Others such as secobaribital are bound to about 50% and some, like warfarin, are about 99% bound. Plasma proteins are capable of binding various acidic compounds such as phenylbutazone, basic compounds such as imipramine, and netural compounds such as digitoxin.
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Most xenobiotics that are bound to plasma proteins bind to albumin. The principal metal binding protein in plasma is ceruloplasmin. The binding of xenobiotics with plasma protein is of special significance in toxicology. Because of their binding with high molecular weight plasma protein, they cannot cross capillary walls and other plasma membranes. Consequently, the bound form of toxicant may not enter the target site to produce injury.
However, addition of another toxic agent can displace the first one from the plasma proteins, thus making it available in free form. For example, if a sulphonamide drug is provided to a patient already taking any diabetic drug, the former replaces the latter and induces hypoglycemic coma.
2. Body Fat as Storage Depot:
Tissues and areas in the body rich in fat tend to store some xenobiotics that are highly soluble in lipids. These chemicals tend to localize in adipose tissues by partitioning between intracellular lipids and body water. Such accumulation in adipose tissue has been demonstrated for a number of xenobiotics, including chlordane, DDT, and polychlorinated and polybrominated biphenyls.
Storage lowers the concentration of the toxicants in the target organ and serves as protective mechanism. Following starvation, the fat mobilization leads to a sharp rise in the plasma concentration of the stored xenobiotics.
Age, sex and race play an important role in the storage (accumulation) of lipid soluble xenobiotics. For example, males accumulate more of organochlorie insecticides than females, older people accumulate more OCIs than young people and Afro- Americans accumulate more of these insecticides than white men.
3. Liver as Storage Depot:
Actually liver may be regarded as a principal storage organ. Since it performs variety of functions viz., storage of glycogen, deamination of amino acids, production of bile, synthesis of blood proteins, synthesis of urea through ornithine cycle and biotransformation, it receives all kinds of molecules from GIT through portal circulation and houses a large amount of all types of xenobiotics as well as proteins, bile and glycogen.
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The xenobiotics, entering liver for the process of biotransformation, bind with different constituents or groups and with other molecules present in the liver, according to their solubility and affinity. Thus liver acts as storage depot for various xenobiotics.
A protein in the cytoplasm of liver cells called ligandin, a γ protein, has been identified which shows a high affinity for many organic acids. Researches reveal that this protein may play a key role in the transfer of organic anions from plasma into liver. This protein also binds azo dye carcinogens and corticosteroids. Metalothionin, another binding protein of liver, binds to the cadmium. Liver is capable of binding lead 50 times greater than plasma within 30 minutes after single administration.
4. Kidney as Storage Depot:
Like liver, kidney has a high capacity for binding multitude of xenobiotics. Since kidney is the principal excretory organ, all kinds of xenobiotics reach kidney glomeruli for filtration. The glomerular basement membrane restricts excretion of protein and lipid molecules, stores various metalloprotein molecules and chlorinated hydrocarbon contaminated fat molecules.
These go on accumulating at this site and cause extensive damage to the kidney glomerular basement membrane. It shall not be out of place to mention that liver and kidney probably concentrate more xenobiotics than do all the other organs combined.
5. Bone as Storage Depot:
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Bone is known to serve as a major storage site for some xenobiotics viz., lead, fluoride, and radioactive strontium. Of these xenobiotics, accumulation of lead in skeletal tissues is more pronounced, as it comprises of about 90% of the total lead in the body. Actually, skeletal uptake of xenobiotics is essentially a surface chemistry phenomenon, with exchange taking place between the bone surface and the fluid in contact with it. Deposition and storage of toxicants in bone may or may not be detrimental.
For instance, lead is not toxic to the bones whereas the accumulation of fluoride for long term exposure causes skeletal flurosis. Likewise, long term storage of radioactive strontium produces osteosarcoma and other neoplasma. Xenobiotics may be released from the bone by ionic exchange at the crystal surface and dissolution of bone crystals through osteoclastic activity.
6. Brain and Nervous Tissues as Storage Depots:
Some xenobiotics have high affinity for the brain tissues. For example, CNS drugs like thiopentone, barbiturates and psychotropic drugs, chlordiazepoxide and chlorpromazine enter the brain tissue rapidly after intravenous administration in experimental animals.
The myelin sheath of axon also accumulates lipid- soluble xenobiotics and acts as storage depot. The axon sheath accumulates a large amount of lipophilic chlorinated hydrocarbons and retains them for long time. Likewise, mercury also accumulates in myelin sheath and produces Hatter’s Shake.
7. Erythrocytes as Storage Depot:
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Pharmacological agents, viz. nitroalamine, becomes localized in the R. B. C. by binding with hemoglobin. Similarly, other xenobiotics, viz. triethyltin (TET) has been reported to bind rapidly with rat hemoglobin. Arsenic, cadmium and lead also localize with erythrocytes for short time.
8. Gonads as Storage Depot:
Researches reveal that epididymal fat of testes and of prostate gland accumulate and store lipid- soluble xenobiotics, example — DDT.
9. Respiratory Tract as Storage Depot:
Xenobiotic molecules may get deposited on the mucosal lining of the respiratory tract and remain trapped there for short time.
10. G.l.T. as Storage Depot:
Various lipid soluble xenobiotics and metals like mercury get deposited and remain trapped in the G.l.T. and accumulate. Also intestinal mucosal lining absorbs lipid soluble xenobiotics and retains them.
11. Gall Bladder as Storage Depot:
Gall bladder acts as storage organ of bile. It also receives and accumulates all kinds of fat-soluble xenobiotic molecules that come from liver and finally pours them into the intestine. In this way, gall bladder also acts as a temporary storage depot.
12. Spleen as Storage Depot:
Spleen being the principal organ for the removal of dead RBCs, also collects large number of RBCs from blood; and along with them, it collects protein binding as well as -SH group binding toxic molecules and stores them for considerable time.
13. Fetus as Storage Depot:
Various lipophilic and hydrophilic xenobiotic molecules cross the placental barrier and reach the fetus. The lipophilic xenobiotics get absorbed in the fat content and accumulate, while hydrophilic molecules get absorbed in the fluid compartments of the fetus and are released slowly.