Glutathione That Conjugation Plays a Significant Role in Kidney Toxicity - Essay Example

Introduction Exposing Kidney to some materials, more so, chemical substances may be harmful to the organ. Often, kidney toxicity refers to harm on the kidney itself, the bladder, or the ureter. Interestingly, the kidney is not very vulnerable to toxicity because filtering injurious materials from the blood is its main role. Nevertheless, chemical materials such as trichloroethylene and other halogenated hydrocarbons as well as heavy metals like lead cause injury to the kidney. These substances may either cause severe harm to the organ, or make alterations that may end in renal malfunction. Research has indicated that glutathione conjugation play a significant role in kidney toxicity, and in particular, the chemically induced nephrotoxicity. The reaction is responsible for bioactivation of potentially halogenated hydrocarbons, which then undergo metabolism with the enzyme beta-lyase-lyase to produce potentially harmful nephrotoxins. Several studies support the link between glutathione conjugation and the toxicity in kidneys. This document, therefore, explores various studies to establish that this reaction and the enzyme beta-lyase-lyase play a role in development of chemically induced nephrotoxicity, and makes a discussion of those roles. The mechanism of glutathione conjugation Glutathione is a tripeptide that is useful in cell protection from toxic substances such as free radicals. Its primary purpose is detoxification through a pathway known as glutathione conjugation. Glutathione conjugation, therefore, is a reaction pathway that involves the bonding of the tripeptide with other compounds. The enzyme glutathione S-transferases plays a vital role in some reactions, more so, in cytosol, mitochondria, and microsomes. Elsewhere, glutathione can participate in conjugation with chemical substances, a process that does not utilize the enzyme glutathione S-transferases. Fig. 1: diagram for a halogenated hydrocarbon (trichloroethylene) metabolism and its significance to renal tubule injury and regeneration (Locks and Reed 2005) The primary steps in glutathione conjugation that utilize glutathione S-transferases available in the microsomes and cytosol of many tissues take place mainly within the liver (Lash et al., 1998). The resulting glutathione S-conjugates are thereafter effortlessly moved into bile and plasma or the small intestine. The glutathione S-conjugates within the intestine or the bile then undergo metabolic reactions to form mercapturates or cysteine S-conjugates accordingly. The kidney then extracts the metabolites (mercapturates or cysteine S-conjugates) through inter-organ pathways for further metabolism or excretion. Furthermore, the Plasma glutathione S-conjugates also go into the kidney before their metabolism or excretion as mercapturates. “The selective tissue distribution of” various enzymes involved in the “glutathione conjugation pathway” as well as ”the plasma membrane transporters” govern the kidney selectivity of the “glutathione-derived metabolites” of chemical substances like Trichloroethylene” (Lash, et al. 1999, 1). The role of glutathione conjugation and beta-lyase in nephrotoxicity The role of glutathione conjugation and enzyme beta-lyase in development of nephrotoxins associated with chemicals is bio-activation. It would be worth to note that the role of glutathione in living things is protection of the cells, which means that they are responsible for detoxification. However, glutathione conjugation with polychlorinated alkenes or halogenated hydrocarbons leads to formation of toxic compounds. Anders, et al. (1988, 320) and Goeptar, et al. (1995, 11) has linked glutathione conjugation with nephrotoxicity of trichloroethylene. Apparently, trichloroethylene forms conjugates with gluatathione, which then cleaves into cysteine S-conjugates that are translocated to the kidney. Therefore, the glutathione reactions are vital for the formation of metabolites that are further metabolised by the beta-lyase-lyase to give electrophilic thioketenes. The electrophilic thioketenes are highly capable of forming covalent bonds with cellular macromolecules. This ability makes them responsible for the particular chemical substance nephrotoxicity. What is more, the glutathione conjugates of the halogenated hydrocarbon that goes to the kidney cause redox reactions or alkylation, which is responsible for the “organ-selective damage” (Dekant 2003). The role of beta -lyase in development of nephrotoxicity is linked to glutathione conjugation. The metabolites that are derived from glutathione conjugation pathway undergo further metabolic reactions with either dipeptidases, gamma-glutamyltransferase, and beta -lyase (or cysteine conjugate beta-lyase). Therefore, the development of nephrotoxins would not be complete because of glutathione conjugation only, but it necessitates the contribution of the beta-lyase or cysteine conjugate beta-lyase. Actually, the enzyme beta-lyase makes the metabolites to be electrophilic so that they combine with cellular macromolecules through covalent bonding. Trichloroethylene and renal toxicity 1, 1, 2-Trichloroethylene is an vital chemical solvent that is widely used in the society. In the 1930’s people used it as an anesthetic. Some studies have revealed that the chemical substance, which is a major contaminant, is toxic to the kidney. Since then, its application as an anethestic has been probihibited. What is more, studies reveal that its metabolism which depends on the glutathione conjugation and enzyme beta-lyase cause the trichloroethylene to be nephrotoxic. Normally, trichloroethylene is not charged, moreover, it is nonpolar and extremely lipophilic meaning it can traverse membranes through diffusion. It is promptly and widely absorbed after either oral intake or inhalation. In addition, it can be absorped through the skin if direct it gets into direct contact with the liquid. Due to its lipophilic nature, trichloroethylene considerably distribute into lipid within the body tissues. Most of it, however, is metabolized in the body. Primarily, cytochromes p450 metabolizes trichloroethylene to “chloral, then to trichloroethanol and its glucurinide, and trichloroacetic acid” (Lock and Reed 2005). Research indicates that these metabolites are eliminated through the urine and, therefore, making trichloroethylene non-harmful to the body tissues and organs. Nevertheless, as further study indicates, trichloroethylene conjugates with glutathione. Studies indicate that some trichloroethylene is excreted as mercapturic acid (or N-acetyl-S-(1, 2-dichlorovinyl)-L-cysteine) through the urine. The mercapturic acid is harmful to the kidney, and it is associated with trichloroethylene conjugation with glutathione as well as the metabolic activities of beta-lyase. Study conducted by Bernauer, et al. (1996), Bloemen, et al. (2001), and Lash, et al. (1999) detected S-(1,2-dichlorovinyl) glutathione and N-acetyl-S-(1, 2-dichlorovinyl)-L-cysteine in urine of participants exposed to trichloroethylene, but in small quantities. That means that glutathione-mediated metabolism is not the main pathway for people exposed to trichloroethylene. Nonetheless, both S-(1, 2-dichlorovinyl) glutathione and S-(1,2-dichlorovinyl)-L-cysteine are toxic to the kidney. Fig. 1: Trichloroethylene bio-activation through glutathione S-transferase and cysteine conjugate beta-lyase: 1) Trichloroethylene, 2) S-(1,2-dichlorovinyl)glutathione, 3) S-(1,2-dichlorovinyl)-L-cysteine, 4) 1,2-dichloroethenethiolate, 5) chlorothioketene 6) S-(1,2-dichlorovinyl)-N-acetyl-L-cysteine, 7) chlorothionoacetyl chloride (Lock and Reeds 2005) S-(1, 2-dichlorovinyl)-L-cysteine was discovered about fifty years ago after extraction of soybean meal with trichloroethylene that was used to feed cattle. Consequently, calves were diagnosed with renal injury and aplastic anemia that was linked to the S-(1, 2-dichlorovinyl)-L-cysteine. Subsequent research, moreover, indicated that S-(1, 2-dichlorovinyl)-L-cysteine was nephrotoxic to several other species. Interestingly, in another studies where synthetic S-(1, 2-dichlorovinyl) glutathione was administered to rats, the results indicated that it was not only nephrotoxic, but also it also changed to S-(1, 2-dichlorovinyl)-L-cysteine before conducting its nephrotoxicity. Literature justification of roles of glutathione conjugation and beta-lyase Several studies have associated glutathione conjugation and enzyme beta-lyase in the development of chemical based nephrotoxicity. Bloemen et al. (2001) confirm that trichloroethylene, a halogenated hydrocarbon, undergoes “conjugation with glutathione” where some is excreted in the urine as N-acetyl-S-(1, 2-dichlorovinyl)-L-cysteine, a mercapturic acid. Note that this acid is renal toxic. Additionally, studies reveals the formation of glutathione S-conjugate with halogenated quinones and alkenes (Lash et al. 2001; Anders, et al. 1998), which progress to become nephrotoxins after a chain of metabolic reactions associated with beta-lyase. The halogenated chemicals include 2-bromo-2-chloro-1, 2-bromohydroquinone, 1- difluoroethene, hexachloro-1, 3-butadiene, and trichloroethene. Further studies have linked the renal toxicity of paracetamol (acetaminophen) and Cisplatin to both glutathione conjugation and beta-lyase. Glutathione, the substrate of enzyme glutathione S-transferase, conjugates in a non-enzymatic process with acetaminophen to form N-acetyl-p-benzoquinone imine – a reactive cytochrome -P450 metabolite. An overdose of paracetamol depletes glutathione thereby making acetaminophen toxic. Similarly, cisplatin forms conjugates with glutathione and undergoes metabolic reactions with beta-lyase. The resulting metabolites are the harmful components to the kidney. Hanigan, et al (2001) illustrates that acivicin prevents the renal toxicity of “cisplatin in rats.” Elsewhere, acivicin inhibits the activities of enzyme gamma-glutamyl transpeptidase, which is a catalyst to the glutathione conjugation pathway. Lash, et al. (1999) asserts that the nephrotoxicity of trichloroethylene is associated with the glutathione conjugation pathway where beta-lyase is used to cleave the metabolite into renal toxins. In fact, the same process of trichloroethylene metabolism has been linked to the development of tumours, thus justifying the substance as carcinogenic. Locks and reeds (2005) consent that trichloroethylene is “an occupational concern”. Dekant (2003) has summarized the transformation of Vicinal dihaloalkanes to nephrotoxins. They are “transformed by glutathione S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl) glutathione S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates formed and interact with nucleic acids.” He further asserts, “Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway”, where after their metabolites are metabolized by renal cystein conjugate beta-lyase to produce metabolites that cause harm to the kidney Dekant (2003). Conclusion The process of glutathione conjugation is a complex reaction that yields metabolites, which become metabolized by the renal beta-lyase-lyase to produce electrophilic compounds. These compounds have high affinity to combine with the cellular compounds hence making them responsible for toxicity. Their redox activities or alkylnation makes is harmful to the kidney. Therefore, the glutathione conjugation pathway and beta-lyase are responsible for bio-activation of chemical substances. Several studies have linked this role of glutathione conjugation and beta-lyase to the development of chemically induced nephrotoxicity. It is the metabolites of the halogenated hydrocarbons, for instance, that cause harm to the organ. S-(1, 2-dichlorovinyl)-L-cysteine and S-(1, 2-dichlorovinyl) glutathione, for example, have been associated with the toxicity of the kidney. References Anders, M. W, Lash L.H, Dekant, W, Elfarra, A. A and Dohn, D. R 1988, Biosynthesis and metabolism of glutathione conjugates to toxic forms, Critical Review Toxicology, vol 18, Medline Journals. Bloemen, L. J, Tomenson, J 2001, Increased incidence of renal cell tumours in a cohort of cardboard workers exposed to trichloroethylene, Arch Toxicology, vol 70, no. 2, PubMed. Dekant, W 2003, Biosynthesis of toxic glutathione conjugates from halogenated alkenes, Toxicology Letters, vol, 144, no.1, Elsevier Science Ireland Ltd., Germany, 13th February 2009, Goeptar, A. R, Commandeur, J. N. M, Van Ommen, B, Van Bladeren, P. J and Vermeulen, N.P. E 1995, Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity, Relevance of the mercapturic acid pathway, Chem Res Toxicology, vol 8, Medline Journals. Hanigan, M. H., Lykissa, E. D., Townsend, D. M., Ou, C., Barrios, R. and Lieberman, M. W 2001, Gamma-Glutamyl Transpeptidase-Deficient Mice Are Resistant to the Nephrotoxic Effects of Cisplatin, American Journal of Pathology, vol, 59, 13th February 2009, Lash, L. H, Fisher, J. W, Lipscomb, J. C, Parker, J. C 2001, Metabolism of trichloroethylene. Environmental Health Perspective., PubMed, vol 177, no. 2. Lash, L. H, Qian, W, Putt, D. A, Jacobs, K. Elfarra, A. A, Krause, R. J, Parker, J. C 1998, Glutathione conjugation of trichloroethylene in rats and mice: sex-, species-, and tissue-dependent differences, Drug metabolism disposition, vol 26, no. 1, Public Medicine, 13th February 2009, Lash, L. H., Lipscomb, J. C., Putt, D. A. and Parker, J. C 1999, Glutathione Conjugation of Trichloroethylene in Human Liver and Kidney - Kinetics and Individual Variation, The American Society for Pharmacology and Experimental Therapeutics journal, vol 27, no. 3, 13th February 2009, Lock, E. A and Reed, C. J 2005, Trichloroethylene: Mechanisms of Renal Toxicity and Renal Cancer and Relevance to Risk Assessment, Toxicological Sciences, vol 91, no. 2, 13th February 1999, Read More

However, glutathione conjugation with polychlorinated alkenes or halogenated hydrocarbons leads to formation of toxic compounds. Anders, et al. (1988, 320) and Goeptar, et al. (1995, 11) has linked glutathione conjugation with nephrotoxicity of trichloroethylene. Apparently, trichloroethylene forms conjugates with gluatathione, which then cleaves into cysteine S-conjugates that are translocated to the kidney. Therefore, the glutathione reactions are vital for the formation of metabolites that are further metabolised by the beta-lyase-lyase to give electrophilic thioketenes.

The electrophilic thioketenes are highly capable of forming covalent bonds with cellular macromolecules. This ability makes them responsible for the particular chemical substance nephrotoxicity. What is more, the glutathione conjugates of the halogenated hydrocarbon that goes to the kidney cause redox reactions or alkylation, which is responsible for the “organ-selective damage” (Dekant 2003). The role of beta -lyase in development of nephrotoxicity is linked to glutathione conjugation.

The metabolites that are derived from glutathione conjugation pathway undergo further metabolic reactions with either dipeptidases, gamma-glutamyltransferase, and beta -lyase (or cysteine conjugate beta-lyase). Therefore, the development of nephrotoxins would not be complete because of glutathione conjugation only, but it necessitates the contribution of the beta-lyase or cysteine conjugate beta-lyase. Actually, the enzyme beta-lyase makes the metabolites to be electrophilic so that they combine with cellular macromolecules through covalent bonding.

Trichloroethylene and renal toxicity 1, 1, 2-Trichloroethylene is an vital chemical solvent that is widely used in the society. In the 1930’s people used it as an anesthetic. Some studies have revealed that the chemical substance, which is a major contaminant, is toxic to the kidney. Since then, its application as an anethestic has been probihibited. What is more, studies reveal that its metabolism which depends on the glutathione conjugation and enzyme beta-lyase cause the trichloroethylene to be nephrotoxic.

Normally, trichloroethylene is not charged, moreover, it is nonpolar and extremely lipophilic meaning it can traverse membranes through diffusion. It is promptly and widely absorbed after either oral intake or inhalation. In addition, it can be absorped through the skin if direct it gets into direct contact with the liquid. Due to its lipophilic nature, trichloroethylene considerably distribute into lipid within the body tissues. Most of it, however, is metabolized in the body. Primarily, cytochromes p450 metabolizes trichloroethylene to “chloral, then to trichloroethanol and its glucurinide, and trichloroacetic acid” (Lock and Reed 2005).

Research indicates that these metabolites are eliminated through the urine and, therefore, making trichloroethylene non-harmful to the body tissues and organs. Nevertheless, as further study indicates, trichloroethylene conjugates with glutathione. Studies indicate that some trichloroethylene is excreted as mercapturic acid (or N-acetyl-S-(1, 2-dichlorovinyl)-L-cysteine) through the urine. The mercapturic acid is harmful to the kidney, and it is associated with trichloroethylene conjugation with glutathione as well as the metabolic activities of beta-lyase.

Study conducted by Bernauer, et al. (1996), Bloemen, et al. (2001), and Lash, et al. (1999) detected S-(1,2-dichlorovinyl) glutathione and N-acetyl-S-(1, 2-dichlorovinyl)-L-cysteine in urine of participants exposed to trichloroethylene, but in small quantities. That means that glutathione-mediated metabolism is not the main pathway for people exposed to trichloroethylene. Nonetheless, both S-(1, 2-dichlorovinyl) glutathione and S-(1,2-dichlorovinyl)-L-cysteine are toxic to the kidney. Fig. 1: Trichloroethylene bio-activation through glutathione S-transferase and cysteine conjugate beta-lyase: 1) Trichloroethylene, 2) S-(1,2-dichlorovinyl)glutathione, 3) S-(1,2-dichlorovinyl)-L-cysteine, 4) 1,2-dichloroethenethiolate, 5) chlorothioketene 6) S-(1,2-dichlorovinyl)-N-acetyl-L-cysteine, 7) chlorothionoacetyl chloride (Lock and Reeds 2005) S-(1, 2-dichlorovinyl)-L-cysteine was discovered about fifty years ago after extraction of soybean meal with trichloroethylene that was used to feed cattle.

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