Lecture 4

Mechanisms of Toxicity

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 Mechanisms of toxicity
• Inhibition of oxygen transport
• Inhibition of electron transport chain
• Irritating, corrosivity
• Inhibition of enzymes
• Penetrating lipid structures, predominantly in the
CNS
• Block of neurotransmission
• Radical damage
• Carcinogenic activity
• Teratogenic activity
 The effect depends on:
• Physical and chemical properties of the substance:
– state, solubility…

• Exposure:
– dose, concentration, duration …

• Organism:
– sex, age, condition…
 Mechanisms of Toxicity
Receptor, ion channel and enzyme-mediated toxicity

Targets
Receptors (4 major superfamilies)
∙ Ligand-gated ion channels ionotropic receptors
voltage-gated ion channels
∙ GPCRs - G protein coupled receptors (metabotropic receptors)
∙ Enzyme-linked receptors (tyrosine kinase activity)
∙ Nuclear receptors (regulate gene transcription)

Enzymes metabolic and catabolic pathways

Carriers uptake/transport systems

Others proteins involved in vesicle release

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 Inhibition of oxygen transport
• CO:
– produced by the incomplete combustion of organic compounds (e.g.
gas)

– binds to hemoglobin ( carboxyhemoglobin) with higher affinity

than oxygen, thus hindering the transport of oxygen

– symptoms:
 at 30-40% of HbCO – headache, dizziness, unconsciousness;
 at 60-65% of HbCO – coma
• Toxicants forming methemoglobin:

– nitrites, derivatives of aniline

– oxidizes iron in hemoglobin from the ferrous (+2) to
ferric (+3) state  Hb is converted to methemoglobin
which is unable to bind O2

– symptoms: cyanosis

– treatment: toluidine blue:

• speeds up the reduction of MetHb to Hb

. Cl-
 Inhibition of electron transport chain

• HCN and cyanides (K-C≡N):

– inhibition of enzymes containing iron, predominantly of cytochrome
oxidase

– symptoms: headache, unconsciousness, respiratory failure

 Irritating gases

• Cl2, HCl, HF, halogen derivatives – some of them are used

as tear gases

– irritate the mucous membranes in the eyes, nose,

mouth and lungs: react with –SH groups of proteins

– symptoms: conjunctivitis, rhinitis, bronchitis, sometimes

even pulmonary edema (phosgene)
 Inhibition of enzymes
• Parathion or sarin:
- Inhibition of Acetylcholinesterase (AChE)
- Build up of acetylcholine in the synaptic cleft
- Large dose lead to: respiratory failure, paralysis

• -amanitin:
– Toxin contained in Amanita Phalloides (Deathcap
mushroom)
– inhibits RNA-polymerase
 liver damage, heart and kidney failure
• Metals:

– react with –SH groups of enzymes

– e.g. lead inhibits enzymes participating in the synthesis of

porphyrin, and thus hematopoiesis

– metals can accumulate in the liver, kidney, and bones

– symptoms: glomerular nephritis, neurological symptoms,

a grey line along the gum (lead, mercury), anemia (lead)
 Block of neurotransmission

• Plant as well as animal toxins

– snake venoms:
 -bungarotoxin – binds to the acetylcholine receptor at the
neuromuscular junction, causing paralysis, respir. failure

– tetrodotoxin – concentrated in internal organs of members of the

order Tetraodontiformes (fish); blocks Na+ channels  paralysis of
the diaphragm, respiratory failure

– curare: alkaloid; blocks neuromuscular transmission  paralysis of

the respiratory muscles
 Corrosivity, acidosis

• Acids:

– local effects (hydrolysis of biomolecules, protein coagulation )

– moreover, intake of H+ can cause acidosis: fall of blood pH

• compensation: hyperventilation, ↑ tubular secretion
of H+
• treatment: neutralization using MgO

• Bases: tissue damage is more severe than by acids

– treatment: large volume of water acidified with a weak acid (acetic)
 Organic solvents:
penetrating the membranes

• Organic solvents can easily penetrate lipid structures of the

cell

• In CNS, they act as anesthetics, sedatives, and hypnotics,

they can cause excitation, inhibition, as well as neurotoxicity

• Halogen derivatives
– chloroform, vinyl chloride
– they can also damage the liver and kidney
 Mechanisms of Toxicity
Organ-Directed Toxicity

• Adverse effects or disease states manifested in specific organs in

the body.

• High cardiac output = higher exposure.

• Organs each have specialized tissues and specialized cells.

• Differentiated cellular processes and receptors.

• Toxicants and metabolites may have specific reactive pathways.

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 Organ- Directed Toxicity

• Toxicants do not affect all organs to the same extent.

• A toxicant may have several sites of action and target organs.

• Multi-toxicant exposure may target the same organ.

• The target organ may not be the site for storage.

• Toxicokinetic processes determine concentrations in target organs.

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 Hepatotoxicity

Organs particularly susceptible to toxin damage are the liver and kidney

Hepatotoxicity
(i) hepatic necrosis
paracetamol poisoning

(ii) hepatic inflammation (hepatitis)

halothane can covalently bind to liver proteins to trigger an
autoimmune reaction

(iii) chronic liver damage (cirrhosis)

long-term ethanol abuse causes cellular toxicity and inflammation and
malnutrition as ethanol becomes a food source

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 Nephrotoxicity

(i) changes in glomerular filration rate (GFR)

Largely due to drugs that alter blood flow :
NSAIDs (eg. aspirin) reduce prostaglandins which in turn reduces
blood flow/GFR
ACE inhibitors (eg. ramipril) increase blood flow/GFR

(ii) allergic nephritis

allergic reaction to NSAIDs (eg. fenoprofen) and antibiotics (eg.
metacillin)

(iii) chronic nephritis

long-term NSAID and paracetamol use

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 Hemotoxicity

• Blood cell components: erythrocytes, leukocytes, thrombocytes.

• Hemotoxicity occurs when the number or function of blood cells

is impaired.

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 Pulmonotoxicity

• Gas exchange function critical to life.

• Rapid exchange, high surface area and sensitivity of mucosal

tissues make the respiratory system susceptible to damage.

• Chemical irritants, carcinogens, allergens, mineral dusts,

cytotoxic chemicals.

• Endpoints: Inflammation, edema, necrosis, fibrosis, carcinoma.

• ARDS, asthma, lung cancer, infarcts, emphysema.

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 Dermotoxicity

• Irritant contact dermatitis

• Allergic contact dermatitis

• Phototoxicity

– UV and a phototoxic compound.

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 Neurotoxicity
• Central nervous system (CNS):

– Brain and spinal cord.

• Peripheral nervous system (PNS).

– Sensory and motor control.

• Neurons:
– Cell body, dendrites, axon.

• Glial cells; structure:

– Astrocytes, nutrient transport

– Oligodendrites/Schwann, myelin

– Microglia, immune function

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 Neurotoxicity, 2

• Can impact Na+/K+ channels.

– Inhibition; stimulation.

• Bind neurotransmitter receptor sites.

• Inhibit enzymes responsible for neurotransmitter

catabolism.

• Damage myelin sheath.

• Morphological (membrane) damage.

• Necrosis
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 Molecular Mechanisms of Toxicology
Mutagenesis and carcinogenesis

A mutagen is a substance or agent that induces heritable change in cells o

r organisms. A carcinogen is a substance that induces unregulated growth
processes in cells or tissues of multicellular animals, leading to cancer.
Mutagenesis refers to processes that result in genetic change, and
carcinogenesis (the processes of tumor development) may result from
mutagenic events.

2 major classes of gene are involved in carcinogenesis:

• Proto-oncogenes: promote cell cycle progression eg. constitutive activity
of growth factor tyrosine-kinase receptors can cause neoplastic
transformation

• Tumour-suppressor genes: inhibit cell cycle progression

eg. mutations in tumor suppression gene product p53 (prevalent in
smokers)
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 Molecular Mechanisms of Toxicology
Mutagenesis and carcinogenesis

Mutagenesis (examples):
Polycyclic aromatic hydrocarbon, nitrosamines, aromatic amines,
alkaloids from plants (Vinca species), benzene

Carcinogenesis ( examples):
Asbestos, arsenic and its compounds, beryllium, cadmium,
hexevalent chromium, ethylene oxide

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 Molecular Mechanisms of Toxicology
Teratogenicity
• Teratogenesis: the creation of birth defects during fetal development
• Teratogens: substances that induce birth defects

Thalidomide Thalidomide
(R)-enantiomer (S)-enantiomer
sedative teratogen
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The thalidomide disaster heralded modern teratogenicity testing

• 1950’s- thalidomide was synthesized by the Grünenthal

• Non-toxic at high doses in all animals species tested

• 1957 - marketed throughout Europe in as Contergan a non-lethal hypnotic

and sedative, recommended as an anti-emetic to treat morning sickness in
pregnant women

• 1961 - thalidomide was the best-selling sleeping pill in West Germany and
the UK

• However, thalidomide produced teratogenic effects in 100% of fetuses

exposed between 3-6 weeks gestation.

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The thalidomide disaster heralded modern teratogenicity testing

• An estimated 8-12,000 infants were born with deformities caused by

thalidomide, and only about 5,000 of these survived beyond childhood

• 1968 - Contergan case was brought to trial

• 1970 - court dismissed the case due to only minor responsibility of

Grünenthal and "minor importance to the public of the Federal
Republic of Germany"

• In fact, thalidomide is a useful drug, used today to treat leprosy and

multiple myeloma (probably due to inhibitory activity on tumour
necrosis factor (TNF)-a production)

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 Mechanisms of Toxicity
Allergic responses

Common form of ADR, usually with a different time course to pharmacological

effects

4 basic clinical syndromes – types I, II, III & IV (Gell & Combes, 1963)

• Type I hypersensitivity reaction – IgE-mediated mast cell degranulation

• Type II antibody-mediated cytotoxic hypersensitivity- involve

haematological reactions i.e. those pertaining to the blood cells
and blood-forming organs

• Type III immune complex-mediated hypersensitivity

• Type IV delayed-type hypersensitivity

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