Glutathione as an antioxidant in inorganic mercury induced nephrotoxicity
Journal of PostGraduate Medicine 2011
This review describes the current understanding and the mechanisms involved by different forms of mercury in eliciting their toxicity in kidney along with the knowledge of major intracellular reductant that plays important role in the mitigation of mercury toxicity for the maintenance of homeostasis within the body of living organisms.
Nephrotoxic: Toxic, or damaging, to the kidney.
Renal: Relating to the kidney. The renal artery is one of two branches of the large blood vessel in the stomach area that serves the kidneys, ureters (tubes that carry urine from the kidney to the bladder) and adrenal glands.
Exposure to mercury has profound effect on renal cellular function and consequently on renal handling of mercury.
Heavy metal toxicity represents an uncommon but clinically significant medical condition, which if unrecognized or inappropriately treated results in significant morbidity and mortality. Among heavy metals, mercury is recognized as a potent and widely distributed toxicant having the ability to accumulate at various levels of food chain besides possessing ability to cross placental and blood-brain barrier. Symptom picture of mercury (Hg 2+ ) toxicity is characterized mainly by a series of renal disorders. Mechanism of inorganic mercury toxicity includes production of reactive oxygen species (ROS) capable of damaging lipids in membrane, proteins or enzymes in tissues, and DNA to induce oxidative stress as balance between generation, and elimination of ROS is essential for maintaining the functional integrity of a cell. Mitigation of endogenous mercury depends as a part on the presence of antioxidants such as glutathione - most abundant intracellular non-protein thiol that plays a central role in the maintenance of cellular redox status by quenching free radicals generated during oxidative stress. Ability of a cell to survive the threat posed by endogenous mercury represents a biological adaptation fundamental to survival. This review describes the current understanding and the mechanisms involved by different forms of mercury in eliciting their toxicity in kidney along with the knowledge of major intracellular reductant that plays important role in the mitigation of mercury toxicity for the maintenance of homeostasis within the body of living organisms.
Mercury - a metal with a widespread use in industries and agriculture - has been recognized as one of the most toxic element, principally in relation to its series of effects on humans following acute or prolonged occupational exposure or from a number of environmental accidents. It has created large havocs in the past, particular being the minimata disaster of Japan and of Iraq. Exposure to mercury is an inescapable consequence of human life. Despite toxic potential of mercury being widely known, its existence in the environment and in several man-made applications makes human exposure inevitable. Concerns regarding potential risk to human population from environmental sources are growing at a steady rate. Mercury toxicity is partly due to its ability to produce a variety of deleterious health effects, ranging from single to multiple target effects inside the body of living organisms. Exposure to mercury has profound effect on renal cellular function and consequently on renal handling of mercury.
Current contentious issue on health risks of mercury underlies a major public health dilemma. Most fascinating of the mercury mysteries is bonding to biological molecules such as proteins, thereby modulating their reactivity as well as their biological effects. Once incorporated in an organism, its physiological and toxicological effects are regulated by two general mechanisms: binding to specific ligands (chelating agents) such as cysteine, homocysteine, GSH, etc., and excretion. Drugs tentatively used as specific chelators against mercury include British Anti-lewisite (BAL), meso-2,3-dimercapto succinic acid (DMSA), sodium salt of 2,3-dimercapto-1-propane sulfonic acid (DMPS), d-penicillamine, etc. However, for being an effective therapeutic chelating agent, it needs to be water-soluble as lipophillic chelators often have a redistribution effect to different organs of the body. GSH, being one of the most versatile and pervasive mercury-binding tripeptide of M-glutamylcysteinyl-glycine, plays an important role in mercury transport, storage, and distribution. Manipulation of intracellular thiols alters accumulation of mercury and as such modulates the effect of mercury at the target site. GSH acts as an important line of defense against oxidative stress as it increases antioxidant capacity of mitochondria, thereby protects it by providing defense against H 2 O 2 , singlet oxygen, hydroxyl radicals, and lipid peroxides generated by mercury. In biological system, binding of mercury with specific ligands such as GSH provides concentration-dependent protection from mercury-induced cytotoxicity as conjugation with GSH limits and regulates its reactivity besides facilitating its transport and elimination from the cell. Despite numerous studies attempted to elucidate the mechanisms implicated in mercury toxicity, further studies are still needed in order to improve pharmacological treatment. Chelating agents such as GSH are the only drugs nowadays available to limit metal toxicity. However, their use is often limited by their lack of selectivity as they cause removal of essential metal ions, thereby making it urgent to identify novel natural substituents that allow the removal of toxic mercury from the body without affecting physiological ionic homeostasis.