Heavy Metals and emerging toxins Flashcards
what is arsenic
Found in earth’s crust with copper, lead and zinc
Also anthropogenic use to preserve timber, in pesticides/ herbicides, cermaic and glass industry
Why was arsenic used as a therapeutic agent since 400 B.C
to treat syphilis prior to availability of antibiotics
Recently As2O3 to treat promyelocytic leukaemia
How is arsenic a toxin
Cell cycle arrest/apoptosis; leads to release of Apoptosis inducing factor (AIF) from mitochondrial intermembrane space
What occurred in West Bengal (India) in the 1960s
Deep wells dug to provide water for irrigation
(Arsenic = natural origin - leached into the water)
>200,000 people effected - cocarcinogen?
‘‘The biggest mass poisoning in history”
why is arsenic so toxic
- manifest itself in virtually all systems
□ Strongly related to oxidation state
□ Trivalent As (reduced) is more toxic than pentavalent arsenic (normal form)
[Trivalent state can be formed when pentavalent is consumed]
□ Mono- and dimethylated forms are more cytotoxic to human cells than their inorganic counterparts
□ Major site of absorption is small intestine (skin absorption is low)
[skin absorption of metal is unpredictables]
why is the symptoms of severe acute arsenic toxicity in humans
gastrointestinal discomfort, vomiting, diarrhoea, bloody urine, anuria, shock, convulsions, coma, and death
Group 1A Carcinogens (Arsenic) manifest itself in virtually all systems. They accumulates in the liver, kidney, heart and lungs causing
□ (haem)angiosarcoma - neoplasm of vessel walls
□ Cardiovascular toxicity (non-cancer) – mechanism unclear; endothelial dysfunction (ROS inhibiting nitric oxide synthase)
□ Neurotoxic effects: Neuritis, Muscle weakness, altered EEG
□ Hyperkeratosis and hyper-pigmentation; skin lesions leading to cancer (squamous, basal, inter-epithelial [Bowen’s disease])
□ Mee’s lines in nails (As deposited in keratin rich tissues)
□ Lung cancer
□ Renal proximal tubule degeneration
how does arsenic cause lung cancer
strong dose response associated with lung cancer
Cancer risk from As appears to be sub-type specific
- In northern chile, SqCC of lung is common amongst non-smokers chronically exposed to arsenic.
- In demark & belgium, no association between cancer incidence and mortality and low level arsenic in drinking water
Carriers of CYP1A1*2A/ GSTM1 homozygous deletion show higher odds ratios for lung cancer
What occurs in the skin when arsenic is consumed
hyperpigmentation or hyperkeratosis causes basal cell or squamous cell carcinoma
or bowen’s disease
How has arsenic been shown to cause cancer
Dose response relationship described
= Keratinocytes exposed to sub/low cytotoxic concentrations exhibit gene expression changes relevant to carcinogenesis e.g Ox stress, growth factors, MAPK, NF-kB
Arsenic is a possible co-carcinogen in the skin
Tobacco smoke/UV
no known mechanism
How is inorganic arsenic metabolised
Arsenate (V) -GSH-> Arsenite (III)
Arsenite (III) is either reversibly undergo GSH OR
-As-Methyltransferase-> Methylarsonic acid MMA(V)
Then MMA(V) is reduced to methylarsonous acid MMA(III)
MMA (III) -As-methyltransferase-> dimethylarsnic acid DMA(V) which is then convert to dimethylarsinious acid DMA(III)
how is inorganic arsenic normally excreted
Urinary excretion
Dimethylarsinic acid DMA(V)
What is the mechanism of action of arsenic in the (V) form
Arsenate can replace phosphate in many biochemical reactions leading to decrease in ATP synthesis
Acts as a glycolysis uncoupler
and creates an unstable intermediate
What is the mechanism of action for arsenic in the (III) form
Very potent binding to -SH group in GSH and cysteine residues in proteins
Methylated forms inhibit pyruvate dehydrogenase and GSH reductase
As III is much loss potent at replacing phosphate, As V is _
much less able to bind SH groups
What is leads
Found in earth’s crust (often with arsenic)
- The most ubiquitous toxic metal
- One of the earliest recognised toxins
- Romans – water pipes, plates, cups, cosmetics, wine sweetener (Pb salts)
how are people exposed to lead
via food/ environment
Released into air from industry; burning fossil fuels, land fill sites
China dishes; amalgam fillings; lead batteries; old plumbing etc
Lead is ubiquitous in the environmental therefore levels
are gradually decreasing but still high in soil (often with As) in areas of industrial
How does lead cause toxicity
Absorbed into blood by divalent metal ion transporter – at least 40% of Pb in blood is bound to proteins in erythrocytes
Can affect almost every organ/system; children most susceptible (Children absorbed more through GI tract than adults). CNS most affected, also kidney and liver.
Cancer (kidney in rodents). Uncertain in man – group 2 carcinogen
How, cellularly, does lead cause toxicity
Inhibits 3 key enzymes in Haem biosynthesis
- Pb enters erthyrocytes via Ca ion channels. Protoporphyrin accumulates in erthyrocytes
- Zn substitutes for iron (ZPP formation) = identifies for lead ingestion
-sigma-Aminolevulinate synthase
-sigma-Aminolevulinate dehydratase
- Ferrocholatase
At high conc of sigma-Aminolevulinate dehydratase inhibition -
protoporphyrin accumulates
How does lead move into the kidneys
Lead, bound to low MW proteins, is filtered by glomerulus and reabsorbed by proximal kidney tubules cells by endocytosis
how does lead cause nephrotoxicity
- Causes mitochondrial damage -> cause the formation of free radicals/ intracellular depletion of GSH = Apoptosis
- Inhibits most enzymes involved in defence against oxidative stress (GSH transferase, reductase, peroxidase, catalase, SOD)
- Affects enzymatic reactions in which calcium plays a role
- Pb induces activation of transcription NFkB causing the activation of the RAAS and attraction of macrophages
- Generates an inflammatory process in the renal interstitium that may be involved in the development of tubulointerstitial damage and high Bp
