الفهرس 
1. INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
The kidney is the main body organ responsible for clearance of endogenous waste products as well as many drugs. That is why the kidney is exposed to a wide variety of potential nephrotoxic substances. Many risk factors account for the vulnerability of the kidney to toxicity including patient- kidney- and drug-related factors. Nephrotoxic substances induce renal damage at different levels: prerenal, intrarenal and postrenal injury. Prerenal injury is caused by drugs affecting kidney perfusion. Intrarenal damage is mediated via exogenous nephrotoxins causing direct damage to the kidney structures such as the glomeruli, epithelium and interstitium. Injury to the collecting system by obstruction leads to postrenal injury. Nephrotoxic injury often happens mainly due to either necrosis or apoptosis. Acute kidney injury (AKI) usually develops within days of exposure to nephrotoxins, while chronic kidney failure takes relatively longer period to occur and its manifestations develop in a slower rate than AKI.
The liver, on the other hand, is the main organ responsible for the metabolism and detoxification of most of drugs. Hepatotoxicity usually happens in cases of drug overdosing or even within therapeutic ranges. Drug hepatotoxicity can be predictable such as in case of acetaminophin or unpredictable and dose unrelated. There are several patterns of drug related hepatotoxicity such as hepatocellular, cholestatic and immune mediated injury. Drug metabolites either electrophilic chemicals or free radicals cause damage via depletion of GSH, covalent binding to proteins, lipids or nucleic acids or causing lipid peroxidation. As a consequence of these reactions, disruption of the functions of cellular organelles follows. Active metabolites can affect cell organelles indirectly by activation or inhibition of enzymes and gene expression.
Reactive oxygen species (ROS) is a collective term that broadly describes oxygen-derived free radicals such as superoxide anion (O2•−), hydroxyl (HO•), peroxyl (RO2•), and alkoxyl (RO•) radicals, as well as oxygen-derived nonradical species such as hydrogen peroxide (H2O2). The mitochondrion is a major intracellular source of ROS. When ROS overwhelm the cellular antioxidant defense system, oxidative stress occurs. Also building up of reactive nitrogen species (RNS) leads to nitosylation of proteins and inhibition of their normal functions. At high concentrations, ROS are able to induce damage to all cellular structures. For example, hydroxyl radicals can react with DNA molecules, peroxyle radicals are involved in lipid peroxidation and the side chains of all amino acid residues are also susceptible to oxidation by ROS/RNS.
Natural cellular defense mechanisms against oxidative stress include many enzymes such as GPx , SOD, and CAT and nonenzymatic antioxidants such as GSH, vitamin C and vitamine E are capable of neutralizing the oxidative damage caused by ROS and RNS. For example, GSH serves as a natural trapping agent for ROS and adequate concentrations are necessary for several physiological processes and SOD catalyzes the breakdown of superoxide anion, so it is considered as a central regulator of ROS levels.
Cyclosporine A is a powerful immunosuppressant that improves graft survival after transplantation surgeries. It is also considered the drug of choice in many autoimmune diseases. CsA is extensively metabolized in the liver by the cytochrome P450 enzyme system. It has many side effects, the most important among them are kidney and liver damage.