Toxic effects of inorganic saltsElaine [email protected], 962-0089Room 2308 Kerr HallSource 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, 10thedition, 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.shtmlMetals and other inorganicsWhy 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 useInorganic Arsenic in Drinking Water“Natural Contamination”• elevated in many places in the USAHuman Industry and Environmental Metals: Lead in Greenland Ice1750 1800 1850 1900 1950 2000050100150200250Lead Content (ng/kg snow)Date of Samples(Modified From: Clarkson et al)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 oxidesMetalloidsTransition (heavy)metalsInner transition metals(rare earths)Other metalsAlkali metalsAlkalineearth metalsTypes of “Metals”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 transportMetals/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 storageMetals 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 deathHighly 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 exposureCdAsNiCrBeExample: Metals/Metalloids Considered Human CarcinogensCarcinogenic 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 homeostasisGeneral 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 disruptionMetals 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 moleculeMolecular Mimicry with Metals: Uptake of Ionic CadmiumControl NEM KCN Zinc024681012Cellular Cadmium UptakeATPZn (+2)Cd (+2)CellSHSHCdZnMolecular MimicryBridges et al., Toxicol. Appl. Pharmacol., (2005), 204: 274-308Molecular Mimicry with Metals; Uptake of OrganomercurialsCH3Hg+ + -S-CH2-CH-COO-NH3+CH3Hg-S-CH2-CH-COO-NH3+methylmercury + cysteinemethylmercury-cysteine complexneutral amino acid carriermethionineHgCH3CellFactors 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 vulnerableFactors 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 depletionFactors 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 effluxInorganics of highest environmental concern:cadmium, mercury, lead and arsenicCadmium• Relatively rare metal present in the earth’s crust • Occurs in only one valency state Cd2+•Used as–