WEEK 7-12 OBJECTIVES

Question 1

Outline the mechanism of action of caffeine.

Answer 1

Adenosine receptors
- G protein-coupled receptors with adenosine as endogenous ligand
- Caffeine is an antagonist at the A1 and A2A receptors

Question 2

Caffeine will lead to

Answer 2

increased heart rate and decreased inhibition of the central nervous system
- Decreasing inhibition of the CNS will increase levels of neurotransmitters such as dopamine and hence it is a stimulant

Question 3

Adenosine receptors are also involved in

Answer 3

sleep-wake cycle (desired effect to stay awake)

Question 4

Caffeine depency

Answer 4

• Generally defined as consumption of over 1000 mg of caffeine every day

Question 5

Symptoms of caffeine dependency

Answer 5

irritability, restlessness, insomnia, headache and heart palpitations

Question 6

Caffeine dependency and cancer/ and other disease or disorder

Answer 6

• Gives a lower overall risk of cancer, but may increase the risk of some specific cancers
  o May also protect against cardiovascular disease, type 2 diabetes and liver disease

Question 7

Caffeine overdose

Answer 7

• Ingestion of over 500 mg caffeine at one time can lead to toxicity

Question 8

initial symptoms of caffeine toxicity

Answer 8

anxiety, insomnia, muscle twitching, heart palpitations

Question 9

extreme doses of caffeine can lead to

Answer 9

mania, depression, hallucination and breakdown of muscle tissues

Question 10

LD50 of caffeine

Answer 10

LD200, so about 100 cups of coffee

Question 11

death cause by (caffeine)

Answer 11

cardiac arrhythmia and arrest

Question 12

Briefly outline the potential risks linked to food preservatives and colourings.

Answer 12

• Artificial preservatives and colouring are controversial, and many have been linked with toxic effects

Question 13

1. What is meant by the term ‘protein substitution’?

Answer 13

Adulterated foods to artificially inflate protein content into a food product

Question 14

Point of protein substitution

Answer 14

o Protein content in food is a highly desirable nutritional quality
o It is also very expensive to produce
o Other nitrogenous non-protein compounds can be added
o These can have potential toxic effects

Question 15

What is the toxic mechanism of action of melamine?

Answer 15

• Metabolism of melamine produces metabolites which crystallise in the kidney and bladder
  o The tubules of the kidney become blocked
  o These cause obstructive urolithiasis (stones), which can lead to renal failure
  o Can also cause bladder cancer and reproductive damage with chronic exposure

Question 16

2. What is meant by the terms ‘surrogate’ and ‘denatured’ alcohols?

Answer 16

o Surrogate alcohols – high level of ethanol (up to 95%)
o Denatured alcohols – ethanol that contains additives to make it poisonous or to give it a foul taste or smell to discourage recreational consumption (10% ethanol)

Question 17

Methanol is a CNS

Answer 17

depresseant

Question 18

methanol affects activity of

Answer 18

NS and brain

Question 19

3. Outline the mechanism of action of methanol.

Answer 19

Stimulation of some inhibitory neurotransmitters (GABA, glycine) and inhibition of stimulatory neurotransmitters

Question 20

What are the two main toxic effects of methanol?

Answer 20

1) stimulation of inhibitory neurotrans and inhibition of simulatory neurotrans
——decrease HR, loss of consciusness
2) Toxication reaction in the liver
——methanol interacts with enzyme alochol dehydrogenase

Question 21

what happens in the toxication reaction of methanol

Answer 21

• In the liver, methanol interacts with the enzyme alcohol dehydrogenase
  o This converts the methanol into formaldehyde
  o Formaldehyde interacts with aldehyde dehydrogenase
• This converts the formaldehyde into formic acid

toxiccc

Question 22

Formic acid toxicity

Formic acid has two main toxic effects:

Answer 22

1. Inhibition of cytochrome c oxidase
   o This causes cellular hypoxia; inhibits ATP production
   o Causes cell death, can target specific cell types such as the optic nerve
2. Metabolic acidosis
   o Production of excess acid in the body that cannot be removed by the kidneys
   Blood pH will drop (< 7.35) leading to coma and death

Question 23

4. What are the two mechanisms of action of thujone?

Answer 23

1) Thujone is an antagonist at the GABAA receptor
2) Thujone also activates 5-aminolevulinic acid synthase

Question 24

1) Thujone is an antagonist at the GABAA receptor

Answer 24

• This prevents inhibition, meaning that the CNS is more sensitive
• While this will have effects throughout the body, the most apparent are muscle spasms and convulsions
  o May also contribute to psychoactive symptoms
• In mice, the LD50 is 45 mg/kg

Question 25

2) Thujone also activates 5-aminolevulinic acid synthase, which catalyses this reaction:

Answer 25

succinyl CoA + glycine ----------> 5-aminolevulinic acid + CO2 + CoASH - 5ALA is the first compound in the synthesis of porphyrins, e.g. haem - Accumulation of porphyrins can lead to porphyria o Symptoms include seizure, pychosis, weakness and extreme pain

Question 26

toxicity of ethylene glycol is not due to the molecule itself, but its

Answer 26

metabolites

Question 26

toxicity of ethylene glycol is not due to the molecule itself, but its

Answer 26

metabolites

Question 27

What are the three main toxic effects of ethylene glycol

Answer 27

1) **Metabolic acidosis** - CNS and cardiovascular dysfunction 2) Oxalic acid binds and inhibits the action of succinate dehydrogenase - **shut down ****TCA cycle ** 3) Associates with Ca2+ to form calcium oxalate - **renal failure and CNS dysfunction**

Question 28

Be sure to describe the physiological consequences of methanol toxicity

Answer 28

- Symptoms occur in three stages: 1. CNS: intoxication, followed by drowsiness or coma; seizures possible (death in 24 hours if dose high) 2. Metabolism: acidosis 3. Kidneys: acute renal failure (death in 2 weeks)

Question 29

how is diethylene glycol different from ethylene glycol in its effects

Answer 29

- Metabolite that causes toxicity is 2-hydroxyethoxyacetic acid (HEAA) - It is likely the HEAA causes **metabolic acidosis** as well as damage to the **kidney and liver** - Symptoms occur in three phases: 1. **Gastrointestinal:** nausea, vomiting; also some CNS symptoms (depression, altered mental status) 2. **Metabolic acidosis:** leads to renal failure 3. **CNS dysfunction:** lethargy, paralysis, coma

Question 30

What are the host factors that affect metal toxicity

Answer 30

1) interaction with essential metals 2) formation of metal-protein complexes 3) age and stage of development 4) lifestyle 5) immune status

Question 31

what are the important metal-binding proteins

Answer 31

1) metallothioneins 2) transferrins 3) ferritin 4) chelation

Question 32

Metallothioneins

Answer 32

o Cysteine-rich proteins attached to Golgi - Bind and regulate physiological metals (Zn, Cu) - Also bind toxic metals (Cd, Hg, Ag, As) o Increased expression on metal exposure o Provide some protection from toxic metals

Question 33

Transferrins

Answer 33

- Plasma iron-binding proteins - Control level of free iron in body fluids - Bind to transferrin receptors and release iron into cell

Question 34

Ferritin

Answer 34

- Intracellular iron-binding protein - Binds to other toxic metals, provides protection

Question 35

Chelation

Answer 35

- Some organic compounds will bind with metals o Used for treatment of metal poisoning - These are called chelating agents o British anti-Lewisite (BAL) o Dimercaptosuccinic acid (DMSA) o Pencillamine o Ethylenediamine tetraacetic acid (EDTA) o Deferoxamine/deferasirox

Question 36

Toxic mechanism of arsenic

Answer 36

binds to thiols (CoA), inhibits pyruvate dehydrogenase (shuts down TCS and leads to ATP depletion, necrosis)

Question 37

Toxic mechanism of lead

Answer 37

binds to sulfhydryl groups (modifies enzyme activity especially neuronal and kidney cells), hijacks Ca transporter (nephrotoxic, degrades myelin sheath of neurons)

Question 38

Toxic mechanism of mercury

Answer 38

irreversibly inhibits selenoenzymes, can also inactivate S-adenosyl-methionine

Question 39

Describe the toxic mechanism of cadmium. Which other metals have the same basic mechanism?

Answer 39

- Inside the cell, Cd causes high levels of H2O2 o Causes oxidative stress - Particularly affects lungs and kidneys o Death usually due to kidney failure o Also causes bones to become soft o Chronic exposure causes cancer - Chromium, copper, copper, iron, nickel

Question 40

5. How does zinc toxicity differ from that caused by cadmium?

Answer 40

- Zinc will cause oxidative stress in cells - Zinc reacts with stomach acid to form corrosive zinc chloride - Nerve receptors in the nose are susceptible o Can cause anosmia o Excess zinc suppresses iron absorption

Question 41

Toxic mechanisms of cobalt

Answer 41

stabilises hypoxia inducible factor (HIF) so mimics effects of hypoxia, causes cell damage and necrosis

Question 42

Toxic mechanism of magnesium

Answer 42

overdose can cause electrolyte imbalance and kidney disorder, can cause cardiac arrest

Question 43

mechanism of action of chlorine gas

Answer 43

- It reacts with water in the lungs to form hydrochloric acid

Question 44

How can chlorine gas be toxic

Answer 44

destroys lung tissue and causes death by asphyxiation

Question 45

mechanism of action of phosgene gas

Answer 45

acts on proteins in the alveoli of the lungs

Question 46

how can phoshene be toxic

Answer 46

- It reacts with the amine groups of the proteins and creates urea-like cross-linkages - This disrupts the blood-air interface, reducing the ability of the lungs to exchange O2 and CO2 - Death is caused by asphyxiation - It also produces HCl which damages lung tissue

Question 47

mechanism of action of mustard gas

Answer 47

- Highly lipophilic, so readily absorbed into the skin o Forms a cyclic sulfonium ion that is very reactive o This ion alkylates guanine nucleotides in DNA, preventing cell division and triggering apoptosis or tumourigenesis o It also causes oxidative damage to the cell

Question 48

toxicity of mustard gas due to

Answer 48

the ion alkylates guanine nucleotides in DNA, preventing cell division and triggering apoptosis or tumourigenesis It also causes oxidative damage to the cell

Question 49

mechanism of lewisite gas

Answer 49

- Arsenite binds to pyruvate dehydrogenase and prevents conversion of pyruvate to acetyl CoA

Question 50

toxicity of lewisite gas

Answer 50

1) shuts down TCA cycle and aerobic respiration 2) lack of ATP leads to weakness and restlessness

Question 51

mechanism of action of nerve gases

Answer 51

AChE inhibitors

Question 52

how nerve gases lead to toxic effects

Answer 52

o It binds to the active site and inactivates the enzyme o Without AChE, ACh builds up in the synapse, preventing the muscle from relaxing then loss of bodily function, spasms, death by respiratory paralysis

Question 53

Two broad types of nerve gas

Answer 53

1. G-series: initially developed in Germany o First developed was tabun o Discovered by the Allies after WWII o Example: sarin 2. V-series: developed by UK, US and Russia o Example: VX gas

Question 54

mechanism of action of dioxins

Answer 54

- Dioxins interact with a specific receptor, the aryl hydrocarbon receptor (AHR) o AHR is a transcription factor, regulating gene expression o Binding of dioxins to AHR induces expression of a group of cytochrome P450 enzymes that break down foreign compounds o These enzymes can also break down important endogenous compounds

Question 55

key effects of dioxins include

Answer 55

1) Immunotoxicity 2) Endocrine disruption 3) Tumour promotion