Heavy Metals

Question 1

Describe arsenic

Answer 1

Found in earths crust
Causes cell cycle arrest and apoptosis due to mitochondrial damage
= release of AIF

Question 2

Describe acute arsenic toxicity

Answer 2

Manifests in virtually all systems = GI discomfort, vomiting, convulsions, anuria

Question 3

How does the oxidation state of arsenic effect is toxicity

Answer 3

Pentavalent in the environment and reduced to trivalent in the body
More toxic as it can inhibit enzymes by imitating other metals

Question 4

What is the most cytotoxic form of arsenic

Answer 4

Methylated forms
E.g mono- and dimethylated forms

Question 5

Where is the main site of arsenic absorption

Answer 5

Small intestine - hijacks metal transporters to get in
Skin absorption too low

Question 6

Describe chronic arsenic toxicity

Answer 6

Group 1A carcinogen
Accumualate in liver, kidney, heart and lungs
Neurotoxic effects
Lung cancer
Renal proximal tubule degeneration
Cardiovascular toxicity

Question 7

What is the effect of arsenic on the skin

Answer 7

Hyperpigmentation or hyperkeratosis = basal cell or squamous cell carcinoma
Exhibits gene expression changes relevant to carcinogenesis
Unsure of mechanism

Question 8

What is the effect of arsenic on the respiratory system

Answer 8

Strong dose response association with lung cancer
Risk appears to sub-type specific

Question 9

What SNP causes carries to have higher odds ratios for lung cancer after exposure to arsenic

Answer 9

CYP1A1*2A
GSTM1 homozygous deletion

Question 10

How are inorganic As metabolised

Answer 10

Arsenate reduced to aresnite
Oxidative metabolism reduces to MMA (V) and restores +5 reduction state
Exhaustively glucuronidated and can be safely excreted as DMA(V)

Question 11

How can As in the +5 state lead to a decrease in ATP synthesis

Answer 11

Glycolysis uncoupler
Arsenate replace phosphate in many biochemical reactions

Question 12

How can As in the +3 state stop you making energy and rapidly deplete GSH supply

Answer 12

Very potent binding to -SH in GSH and cysteine residues in proteins
Methylated form also inhibits pyruvate dehydrogenase and GSH reductase

Question 13

What mechanism cause arsenic toxicity at cellular levels

Answer 13

Mainly its ability to inactivate enzymes especially those involved in cellular energy pathways, GSH synthesis and DNA synthesis/repair