Cadmium Nickel Cyanide Flashcards
Cadmium(Cd)
About 75% is produced in batteries(NiCad)
Also in rust protection and color pigment and plastic stablizer
Food is major source bc plants,shellfish,smoking,welders accumulate
Absorption:
GIT limited 5-10%:via divalent metal ion transporter 1(DMT2)-also tran lead + ni
Inc in diets deficient in iron(due to upregulation of protein)
Women tend to have higher blood level than men(bc women need more iron)
Absorption through inhalation is generally greater-up to 35%
If particle size allow, can penetrate to alveoli where almost 100% in blood
Primary deposited in liver and less extent in kidney(but more sensitive)
Cd toxicity
Acute:
If ingested severe GIT disturbance-PAINFUL ANAL SPHINCTER SPASMS(specific Cd), excess salivation
Mucosa slough off=bloody diarrhea
Inhalation produces acute pneumonitis w/ pulmonary edema and can = death
Can be fatal if inhaled large doses
Chronic
Nephrotoxicity-prox tubule damage(inc SMW protein)
Obstructive pulmonary disease(fibrosis, emphysema-irreversible)
Osteoporosis/osteomalacia-Spontaneous fractures=painful and debilitating due to loss of VitD binding P, renal calcium reabsorption issues
CVD
Cancer
Mech of Cd2+ toxicity
Overall, binds to sulfhydryl groups of protein
Differentially affects mitochondrial proteins
Impared func of adhesion protein
Impaired glucose transport
Downreg of Na+-dependent glucose transporter expression
Due to substitution for Zn2+ in transcription factor (Sp1)
Mito tox
Deplete antiox thiols=oxidative stress
Induce MPT, release cyt C
Apop by mito path
Carcinogenesis
Affect enzyme that methylates DNA(DNMT1)-alter transcription of TSG
Cd and Metallothionein***
Metallothionein: is a p found in many tissues(Kidney, liver, spleen, heart, lung and brain
Expression can be induced by: Cd2+, Zn2+, Hg2+
Acts to bind and sequester these metals(7 metal: 20 cysteines)
t1/2 of MT-bound Cd is 10-30yr-stay in liver
- AT hi level, binds GSH
- At low level, binds MT
Management of Cd Poisoning
NO TREATMENT PROTOCOLS EXIST
Most are supportive care only
Chelator = ineffective
EDTA may be beneficial in single dose cases- shows INCREASE nephrotoxicity after repeated Cd exposure
BAL Increase nephrotoxicity - increase uptake by kidneys
DMSA sometimes used if cadmium was ingested to prevent further absorption
Though that chelat therapy may act to redistribute cadmium to other organs by stripping it away from MT
A number of cases has shown improvement with glutathione** A case found improvement and prevent escalating tox when GSH and EDTA administered together
Nickel(Ni)
Combo with CO to form Ni(CO)4 = toxic
Inhaled as vapor and rapidly absorbed
Accumulate connective tissue of lungs
Intox can develop hours or even days after exposure with initially mild symptoms
Primary tox is via GSH depletion and binding to prot SH group
PRIMARY INJURY is to alveoli, max damage occur 4-6 days after exposure
Carcinogenicity of Ni
Ni carcinogens in respiratory system-nasal and lung cancer
Ni containing particle phags by target cell and then stored in ACIDIC VACUOLES(lysosomes)-release it as nickel
Results in hi intracell conc in both cytoplasmic(insoluble) and nucleus(soluble)
Mech of Ni carcinogenicity
Phag particles that deliver high conc to nucleus are typically clastogenic(break chrome) rather than mutagenic
Crystalline nickel sulfide compounds produce specific chromosomal damage esp. In long arm of X chromosome-decondensation, frequent deletions
Clastogenic mech unclear but it seems to relate to fact that Ni can affect calcium entry into the cell and intracellular levels of calcium
Calcium chelator inhibit nickel-induced clastogenisis
Epigenetic effects- change in gene expression not caused of DNA alteration
Some genes show increase expression in presence of Ni:
HIF-1(hypoxia inducible factor)-inc angiogenesis and glucose transport-shift organism from aerobic to anaerobic metab
Ect2(Control DNA synth)-MT disassembly results in morphological changes
Ni can alter methylation of genes including TS by replacing ferrous iron in catalytic centres of histone demethylase and DNA repair enzymes-silence genes
How?
Proposed that Ni replace Zn in zinc fingers-normally found in DNA binding p
Nickel poisoning management
Chelation therapy and supportive measures-DDC(diethyldithiocarbamate)
Disulfiram-prodrug of 2 DDC molec
EDTA not effective***
Cyanide
HCN Combustion product of plastic, wool and other nat synthetic substance
- 250mg fatal oral
- Breathed in HCN v toxic, swallowed or absorbed through skin and mucous membrane
Cyanide poisoning
Bitter almond smell
May or may not be noticed-smell is genetic
Cig smoke increase chance
Effect of cyanide
Abrupt onset of serious symptoms is hallmark effect-less than one minute inhale, few ingest-”hypoxia”
Hyperventilation, rapid deep breath, confusion
Tachycardia
Rapid loss of consciousness
CV collapse
Resp failure
Death
Quackery
Laetrile, B17 sold as cancer therapy-banned in US and Canada
Modified version of amygdalin-found in peach and almond pits
Cyanide released when endogenous BETA-GLUCOSIDASE removes the suga
Mech of cyanide toxicity
Primary mech of tox is prevention of mito oxygen utilization
CN reversibly binds to ferric iron in Cytochrome oxidase a3-COMPLEX 4
This inhibit oxidative phosphorylation-body shifts to anaerobic metab which increase lactic acid production=acidosis
Cells are hypoxic even if there are normal O2 levels in blood tests=tissue depend heavily on oxygen-Brain and heart typically affected first
CN therapy-nitrites and thiosulfate
Nitrite + thiosulfate = synergistic
Nitrite: convert Hb to metHb
CN prefers to bind Fe3+ in metHB compared to Fe3+ in cyt a3
Thiosulfate: help in CN clearance
Acts as sulfur donor in a rxn catalyzed by rhodanese=thiocyanate is formed=pee
