Toxic effects of inorganic salts Elaine Leslie eleslie email unc edu 962 0089 Room 2308 Kerr Hall Source and Supplemental Material not reading assignments Klassen CD Heavy metals and heavy metal antagonists In Hardman JG Limbird LL eds Goodman and Gilman s The Pharmacological Basis of Therapeutics 10th edition Chapter 67 McGraw Hill 2001 Bhattacharyya MH et al Biochemical Pathways in Cadmium Toxicity In Zalups RK and Koropatnick J eds Molecular Biology and Toxicology of Metals Chapter 2 Taylor and Francis 2000 Tchounwou et al 2003 Environmental Exposure to Mercury and Its Toxicopathologic Implications for Public Health Envirn Toxicol 18 149 175 http www dartmouth edu toxmetal HM shtml Metals and other inorganics Why are they of such concern Widely distributed in the natural environment Non biodegradable and persistent in the environment Neither created nor destroyed by humans Concentrated due to industrial use Global dispersion due to human use Inorganic Arsenic in Drinking Water Natural Contamination elevated in many places in the USA Human Industry and Environmental Metals Lead in Greenland Ice Lead Content ng kg snow 250 200 150 100 50 0 1750 1800 1850 1900 Date of Samples Modified From Clarkson et al 1950 2000 What is a Metal Physical properties electrical conductivity thermal conductivity luster deformed without cleavage under stress Chemical properties tendency to donate electrons cationic formation of basic oxides Types of Metals Alkali metals Metalloids Alkaline earth metals Other metals Transition heavy metals Inner transition metals rare earths Essential Metals Examples of essential metal nutrients Cu Fe Zn Examples of metal functions that are essential to life regulation of gene expression DNA synthesis and repair enzyme activity and structure oxygen transport Metals Metalloids as Toxic Agents Essential metals have intentional accumulation transport and storage mechanisms to prevent cellular damage Examples metallothionein for copper or zinc storage transferrin and ferritin for iron transport and storage Metals as Toxic Agents Exposure to toxic metals metalloids generally results in disruption of enzyme systems High affinity for sufhydryl residues Cysteine residues Acute doses can result in disruption of ATP synthesis at the cellular level and ultimately cause death Highly Toxic Inorganics Metals considered highly toxic include arsenic beryllium cadmium chromium lead mercury and nickel Many are potent neurotoxins acute and chronic exposure e g lead 5 inorganics are considered human carcinogens Chronic exposure Example Metals Metalloids Considered Human Carcinogens As Be Cr Ni Cd Carcinogenic Metals Metalloids Known human carcinogenic metals arsenic skin bladder lung liver beryllium lung cadmium lung chromium lung sino nasal cavity nickel lung sino nasal cavity General Mechanisms of Metal Toxicology direct binding to cellular components direct binding leading to dysfunction enzyme inhibition DNA adduction etc direct binding leading to aberrant function gene activation receptor activation etc direct binding through mimicry leading to displacement of essential metal adverse effect of released essential metal disrupted homeostasis General Mechanisms of Metal Toxicology disruption of normal cellular metabolism leading to aberrant metabolism or altered homeostasis frequently occur through atomic or molecular mimicry examples disruption of essential metal metabolism depletion of cofactors e g S adenosyl methionine depletion of GSH could result in altered cellular redox status etc General Mechanisms of Metal Toxicology continued indirect attack on cellular components generation of radicals that attack cellular components directly with redox active metals eg Ni Cr Cu etc indirectly with metals that displace redox active essential metals eg Fe Cu adverse effects of radical attack disruption of protein conformation leading to dysfunction diminished or enhanced oxidative DNA damage or base modification leading to aberrant gene expression or mutation lipid peroxidation and membrane disruption Metals as Toxic Agents Toxic metals often follow essential metals Metabolic pathways Transport pathways for cellular entry This molecular mimicry can Occur with the ionic form e g Cd2 cellular uptake via Ca2 channels or Zn2 transporters In combination with an organic molecule Molecular Mimicry with Metals Uptake of Ionic Cadmium Cell Cellular Cadmium Uptake 12 10 8 Cd Cd 2 6 4 ATP Zn 2 2 0 Control NEM KCN Zinc SH SH Zn Molecular Mimicry Bridges et al Toxicol Appl Pharmacol 2005 204 274 308 Molecular Mimicry with Metals Uptake of Organomercurials Cell methylmercury cysteine CH3Hg S CH 2 CH COO HgCH3 NH3 CH3Hg S CH2 CH COONH3 methylmercury cysteine complex neutral amino acid carrier methionine Factors Influencing Metal Toxicity Sensitive Subpopulations and Environmental Exposure Sensitive subpopulations have been observed in several diseases induced by environmental metal exposure Examples Minimata disease in utero exposed populations most affected Itai Itai disease post menopausal multiparous women most affected Lead toxicity children much more vulnerable Factors Influencing Metal Toxicity Sensitive Subpopulations and Environmental Exposure Deficiencies in essential metals can result in exposure to toxic metals Fe2 Ca2 deficiency can result in increased expression of intestinal uptake transport proteins and channels which also allow toxic metals to enter the body e g divalent metal transporter 1 DMT1 transports Fe2 Cd2 and Pb2 General malnourishment can also susceptibility Protein deficiencies GSH depletion Factors Influencing Metal Toxicity Acquired Tolerance Examples enhanced sequestration activation of MT gene and cadmium sequestration reduced uptake or enhanced excretion arsenic nickel cadmium altered metabolism arsenic and upregulation of glutathione S transferase facilitates efflux Inorganics of highest environmental concern cadmium mercury lead and arsenic Cadmium Relatively rare metal present in the earth s crust Occurs in only one valency state Cd2 Used as Protective coating on steel Colored pigments in paints and plastics bright yellow orange and red Rechargeable nickel cadmium batteries Biproduct of burning fossil fuels esp coal Exposure workplace food cigarette smoke 1 2 g cigarette plants accumulate Cd in leaves Cadmium accumulates in body over time increases with age 50 years of age kidney Cd concentrations Smoker 25 g g Non smoker 12 g g Targets Kidney more on mechanism Lung