Naslov
Cellular mechanisms of heavy metal toxicity

Autori
Herak-Kramberger, Carol Mirna

Vrsta, podvrsta i kategorija rada
Radovi u zbornicima skupova, cjeloviti rad (in extenso), znanstveni

Izvornik
Farmacevtski vestnik / Andrijana Tivadar - Ljubljana : Slovensko farmacevtsko društvo, 2004, 315-316

Skup
16th International Symposium of Slovenian Association for Clinical Chemistry and Croatian Society of Medical Biochemists

Mjesto i datum
Maribor, Slovenija, 15.10.2004. - 16.10.2004

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
heavy metals; cadmium; nephrotoxicity; brush-border membrane; endocytosis

Sažetak
Cellular mechanisms of heavy metal toxicity Carol Mirna Herak-Kramberger, Institute for Medical Research and Occupational Health, Zagreb, Croatia Metals are natural constituents of the environment and their balance is obtained by both geologic and biologic cycles. Human activity interferes with these natural cycles causing a redistribution of metals worldwide. Utilization of metals by humans influences their potential for health effects in at least two major ways: first, by environmental transport , that is by human or anthropogenic contributions to air, water, soil and food, and second, by altering the speciation or biochemical form of the element. Heavy metals, such as cadmium, mercury, lead, arsenic and platinum, exhibit various toxic effects in mammals. Main exposure sources of these metals are air, food and water. Following absorption in the lungs or gastro-intestinal tract, metals are transported and distributed to their target sites (1). Most metals affect multiple organ systems, but each metal has a critical effect seen in a specific organ or tissue, resulting in their dysfunction. The most prominent adverse effects of heavy metals in mammals are hepatotoxicity, nephrotoxicity, neurotoxicity, genotoxicity and carcinogenesis. The functional integrity of the mammalian kidney is vital to total body homeostasis, as the kidney plays a principal role in the excretion of metabolic wastes and in the regulation of extracellular fluid volume, electrolyte composition, and acid-base balance. Therefore, a toxic insult to the kidney could disrupt any or all of its functions and could have profound effects on total body metabolism. Nephrotoxicity in humans and experimental animals due to exposure to cadmium, mercury and platinum is primarily manifested by impaired reabsorption and secretion in proximal tubules (2, 3). Cadmium induced nephropathy clinically resembles acquired Fanconi syndrome, including polyuria, proteinuria, phosphaturia, aminoaciduria, and glucosuria. The symptoms indicate that the primary target for this metal might be the plasma membrane, i.e. various transporters localized in the brush-border membrane (4). The cellular mechanisms of heavy metal nephrotoxicity are poorly understood. In order to investigate the underlying events leading to malfunction of proximal tubules, we used experimental rat models of a fully developed cadmium (mercury or cis-platinum) nephropathy (4, 5). By immunoblotting of brush-border membranes isolated from rat kidneys (6) and by indirect immunocytochemistry in 4  m-thick frozen fixed kidney sections, we studied the expression of various transporters in cadmium-treated rats. Using these methods, we also studied the effect of heavy metals on the expression and structure of the cytoskeleton. Experimental evidence in experimental cadmium nephropathy in rats led us to conclusion that impaired reabsorptive and secretory functions of proximal tubules in heavy metal nephrotoxicity may result from: a) shortening and loss of microvilli (7, 8), b) direct inhibition of brush-border transporters (4, 9) c) loss of specific transporters from the membrane (4, 7), and d) combination of these phenomena. Loss of brush-border membrane transporters may be the result of impaired vesicle-mediated recycling (endo- and exocytosis) of membrane proteins in proximal tubular cells, due to diminished expression of the vacuolar H+-ATPase and direct inhibition of its activity in intracellular organelles (7). In addition, cadmium, mercury and platinum were found to affect the structure, polymerization state and abundance of cytoskeleton in proximal tubule cells (5). Since microtubules are involved in vesicle trafficking and maintaining epithelial cell polarity (10), depolymerization of microtubules may have deleterious consequences with regard to the structure and function of proximal tubule cells. In concert with a functional V-ATPase, microtubules are inevitable for the continuous recycling of various domain-specific membrane proteins and their functional integration into the brush-border membrane. 1. Goyer RA. In: Cassarett & Doull's Toxicology. The basic science of poisons 5th ed. New York: McGraw-Hill, 1996: 691-736. 2. Goldstein RS and RG Schnellmann. In: Cassarett & Doull's Toxicology. The basic science of poisons 5th ed. New York: McGraw-Hill, 1996: 417-442. 3. Lock EA. In: General and applied toxicology Vol. 3. 2nd ed. London: MacMillan Reference Ltd., 1999: 675-700. 4. Herak-Kramberger CM, Spindler B, Biber J et al. Renal type II Na/Pi-cotransporter is strongly impaired whereas the Na/sulphate-cotransporter and aquaporin 1 are unchanged in cadmium-treated rats. Pfluegers Arch – Eur J Physiol 1996 ; 432: 336-344. 5. Sabolić I, Ljubojević M, Herak-Kramberger CM et al. Cd-MT causes endocytosis of brush-border transporters in rat renal proximal tubules. Am J Physiol Renal Physiol 2002 ; 283: F1389-F1402. 6. Biber J, Stieger B, Haase W et al. A high yield preparation for rat kidney brush-border membranes ; different bahavior of lysosomal markers. Biochim Biophys Acta 1981 ; 647: 169-176. 7. Herak-Kramberger CM and I Sabolić. Cadmium inhibits vacuolar H+-ATPase and endocytosis in rat kidney cortex. Kidney Int 1998 ; 53: 1713-1726. 8. Condron RJ, Schroen CJ and AT Marshall. Morphometric analysis of renal proximal tubules in cadmium-treated rats. J Submicroc Cytol Pathol 1984 ; 26: 51-58. 9. Ahn W, Kim YK, KR Kim et al. Cadmium binding and soium-dependent solution transport in renal brush-border membrane vesicles. Toxicol Appl Pharmacol 1999 ; 154: 212-218. 10. Brown D and JL Stow. Protein trafficking and polarity in kidney epithelium: from cell biology to physiology. Physiol Rev 1998 ; 76: 245-297.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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