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AP0510 Medical Biochemistry > Toxicology > Flashcards

Toxicology Flashcards

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USMLE® Step 1 flashcards
1
Q

Toxicology

A
  • study of potential harmful effects of chemicals on living organisms, biological systems and human health
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2
Q

Examples of toxic substances

A
  • Drugs and their metabolites
  • Chemical substances, classified by their source of exposure: occupational, environmental, household
  • Pesticides (certainly toxic to at least one life form)
  • Natural toxins (e.g. snake venom)
  • Food additives (some E-numbers) and contaminants (e.g. melamine contamination of baby formula)
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3
Q

Thalidomide

A
  • Prescribed to relieve morning sickness during pregnancy – placental delivery unknown
  • Introduced in 1956
  • World-wide increase in malformations in new-borns
  • Mainly phocomelia (shortening of limbs)
  • Withdrawn in 1961 after link between the malformations and Thalidomide was proven
  • Resulted in much more rigorous drug testing before licence is granted
  • Now licensed for leprosy; multiple myeloma
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4
Q

Occupational Toxicology: Examples

A
  • Chimney sweeps’ carcinoma: scrotal cancer due to prolonged exposure to polyaromatic hydrocarbons (PAHs) present in soot
  • Nasal carcinomas in wood workers due to PAHs formed during sawing and sanding (incomplete combustion due to friction-based heat generation)
  • Bladder cancer in dye workers due to use of naphtylamine, an azodye precursor (nowadays largely replaced by less carcinogenic alternatives)
  • Neuropathy as result of long-term exposure to hexane (leather workers) or carbon disulphide (nylon workers)
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5
Q

Lungs as a susceptible organ

A
  • Highly perfused, receive 100% of right side cardiac output
  • Exposed to high concentration of molecular oxygen
  • Metabolic activity (local or in liver) can lead to formation of reactive metabolites
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6
Q

Liver as a susceptible organ

A
  • Receives 80% of blood supply from portal circulation, exposed to highest concentration of ingested xenobiotics
  • Most important concentration of metabolic activity – inducers of CYPs and/or inhibitors can have significant effects on ‘capacity’ to deal with toxic substances
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7
Q

Kidneys as a susceptible organ

A
  • Highly perfused, only 5% of body weight but receives 25% of right side cardiac output
  • Glomerular filtrate is highly concentrated (to drive reabsorption) – non-toxic compounds in plasma may reach toxic concentrations in tubular fluid
  • Ionic chemicals require active transport to be re-absorbed – non specific transport can lead to reabsorption of toxic chemicals
  • Metabolic activity can lead to formation of reactive metabolites
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8
Q

Central nervous system

A
  • Highly perfused
  • Blood brain barrier not 100% effective
  • Efflux transporters require ATP
  • Neurons have high metabolic rate, high mitochondrial activity
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9
Q

Acute toxic effects

A
  • Rapid development whilst chemicals or metabolites are still in body
  • Short lived - may be lethal
  • May result from single or short term exposure
  • Cause and effect easily identified
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10
Q

Chronic toxic effects

A
  • Delayed development - develops after chemical excreted
  • Retrospective detection by epidemiology
  • May result from single, multiple or chronic exposure
  • May be cumulative effect from long term low level exposure e.g. cancer, neurodegenerative diseases
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11
Q

Visible/detectable cause of toxic effects

A 
- exposure to toxic substance
Absorption via: gastro-intestinal tract, respiratory system, skin contact
- distribution
- metabolism
- elimination
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12
Q

Visible/detectable effects of toxicity

A 
- primary target
(biomolecular interaction/reaction)
- cell damage
- organ damage
- adverse effect on organism (disease)
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13
Q

ADME

A
  • Absorption: how chemical enters the body and systemic circulation
  • Distribution: how chemical is distributed in the systemic circulation to the rest of the body
  • Metabolism: what happens to chemical inside the body
  • Elimination: how the parent chemical or metabolite leaves the body (urine, faeces, other)
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14
Q

Absorption (pharmokinetics)

A
  • great majority of therapeutics are orally administered
  • absorbed through buccal/oral mucosa, stomach and/or intestine
  • pH differs in these compartments differences in ionisation state of drugs e.g. salicylate
  • non-ionized forms are more readily absorbed – more easily cross cell membranes
  • Most absorption occurs in intestine
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15
Q

Absorption of Aspirin

A
  • uptake via the stomach

- near neutral pH of blood ensures that aspirin is ‘locked’

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16
Q

Absorption of Morphine

A
  • Ionized in the stomach – no absorption
  • pKa is within the intestinal pH range, resulting in absorption
  • Many drugs contain an amine-based ionizable group with similar pKa to facilitate intestinal uptake
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17
Q

Distribution (pharmokinetics)

A
  • Initial phase happens rapidly as a factor of blood flow to organs and tissues
  • Some tissues are highly perfused (lungs, brain, liver, kidney)
  • Liver receives 80% of blood via the portal system
  • Subsequent uptake by tissues/organs is largely dependent on “affinity”
  • Ability to cross biological membranes
  • Specific transporters (influx and efflux)
  • Protein binding
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18
Q

Blood-brain barrier

A
  • Not an absolute barrier
  • Interstitial fluid has a lower protein content than plasma
  • Capillary endothelial cells tightly joined
  • Transmembrane transporters: efflux
  • Endothelial cells surrounded by glial cells: lipid membranes of glial cell processes a significant barrier
  • “Gaps in BBB” e.g. pituitary gland, choroid plexus, olfactory bulb
19
Q

Phase I of mechanism of xenobiotics

A
  • Modification: Oxidation (e.g. P450 monooxygenases), Reductions (e.g. alcohol/aldehyde dehydrogenase), Hydrolysis (e.g. esterase, epoxide hydrolase)
  • Can result in activated or deactivated xenobiotic
  • Interaction with/modification of biomolecular target –> toxic effects
20
Q

Phase II of mechanism of antibiotics

A
  • Covalent modification of xenobiotics (and other ‘waste’ molecules e.g. bilirubin) with high molecular weight, polar, highly water soluble groups: Glucuronide (from UDP glucuronic acid), Glutathione (from reduced glutathione), Sulphate (from 3’-phosphoadenosine-5-phosphosulphate), Acetate (from acetyl CoA)
  • Greatly increases efficiency of excretion, especially in bile, but also urine
21
Q

Cytochrome P450 (CYP450)

A
  • multigene superfamily: 37 different multigene families, 10 are known in mammals, 8 in humans
  • More than 300 isoenzymes, relatively low substrate specificity, so broad range of reactions possible
  • Inhibition can have severe pharmacological consequences: Deactivation (clearance rate decreases, increasing risk of adverse effects or even resulting in overdoses), Activation (drugs lose their therapeutic action)
  • Four enzyme families play role in metabolism – CYP1-4
  • contain Haem: characterised by absorbance at 450 nm when CO is bound
  • CYP450 enzymes require a reductase for providing electrons
  • Microsomal enzymes: associated to the ER membrane via a membrane anchor
22
Q

Mono-oxygenation of CYP450

A
  • Oxidation of a broad range of compounds in order to (ultimately) functionalize them
  • Generic reaction scheme:
    R + O2 + NADPH + H+ –> RO + H2O + NADP+
  • example reactions: aliphatic hydroxylation, N-hydroxylation, sulfoxidation
23
Q

Epoxidation of CYP450

A
  • Mono-oxygenation of a carbon-carbon double bond
  • Epoxides are typically more reactive and can cause severe damage to biomolecules
  • Hydrolysis of epoxides into vicinal diols by microsomal epoxide hydrolase (mEH) crucial to prevent damage by reactive epoxides
24
Q

Phosphotriesterase activity by paraoxonase 1 (PON1)

A
  • Phase I enzyme
  • Detoxifies organophosphates (e.g. pesticides, nerve gases)
  • PON1 is also an anti-atherosclerotic component of high-density lipoprotein (HDL)
25
Q

Oxidoreductives

A
  • Alcohol dehydrogenase (ADH)
  • Aldehyde dehydrogenase (ALDH)
  • Flavin mononucleotide oxygenases
  • NADP(H) Quinone reductases
26
Q

Glucuronidation

A
  • Modification of amine (-N) and hydroxyl (-O) groups in compounds to improve solubility
  • Responsible enzymes: UDP-glucuronosyltransferases (UGTs)
  • donor substrate - GlcA-UDP
27
Q

Glutathionylation

A
  • Nucleophilic attack of sulphur group on electrophilic centers in a variety of substrates
  • Responsible enzymes: glutathione-S-transferases (GSTs)
  • donor substrate - GSH
28
Q

Sulphation

A
  • Modification of amine (-N) and hydroxyl (-O) groups to improve solubility
  • Similar purpose as glucuronidation
  • Responsible enzymes: sulfotransferases (STs)
  • donor substrate - PAPS
  • Generic reactions: sulfation of alcohols and amines
29
Q

Acetylation

A
  • Modification of arylamino compounds
  • Responsible enzymes: N-acetyltransferases (NATs)
  • donor substrate – Acetyl-CoA
  • Generic reaction: N-acetylation of aniline
30
Q

Metabolism

A
  • Main organ for detoxification: the liver
  • Most xenobiotics enter body via oral ingestion and enter circulation via intestines, i.e. enter circulation in portal vein
  • Contains high levels of several phase I enzymes and conjugating enzymes
  • Some other organs (need to) possess their own metabolic capacity (may differ from liver in specificity and activity) due to high perfusion and:
  • Lungs and skin: part of bodies ‘defence’, can be ‘attacked’ without liver being able to ‘intervene’
  • Kidney: mechanism of action can cause increases in concentration of xenobiotics, reaching toxic levels
  • Some enzymes (CYPs and transferases) exhibit polymorphisms: ideally, drugs should be metabolised by a variety of CYP isoforms
31
Q

Elimination

A
  • Conjugated metabolites can be excreted via two routes: urine via the kidneys (the major route), biliary route - avoids exposure of other organs via systemic circulation, i.e. liver acts as a gatekeeper
  • Certain metabolites may de-conjugate in bile (result of enzymatic activity of gut microflora) and hence be available for re-absorption – enterohepatic recirculation
  • De-conjugation may also occur in the bladder.
32
Q

Metabolic/Cellular consequences in mechanism of toxicity

A
  • Dysregulation of cellular homeostasis, mitochondrial function, cell cycle and others
  • Cytotoxicity: necrosis and/or apoptosis
  • Genotoxicity (direct or indirect)
33
Q

Molecular Mechanisms in toxicity

A
  • Oxidative stress and generation of reactive oxygen species

- Reactive parent chemicals or metabolites which bind to macromolecules such as proteins and/or DNA

34
Q

Un-stressed cell

A
  • High levels of reduced glutathione - reduced environment within the cell
  • Reduced thiols on proteins
  • Anti-oxidants and enzymes available to protect cell
  • Oxidatively damaged DNA bases are repaired
35
Q

Oxidative stress

A
  • imbalance between cellular production of reactive oxygen species (ROS) and the ability to detoxify ROS/ability to repair damage
36
Q

Formation of ROS

A
  • Molecular oxygen can accept electrons to give ROS such as hydrogen peroxide, superoxide and the hydroxyl radical
  • Fenton reaction generates most toxic ROS: the hydroxyl radical
  • Factors that drive the Fenton reaction: Directly (high levels of hydrogen peroxide and freely available Fe2+), Indirectly (superoxide)
37
Q

Remove hydrogen peroxide and superoxide (defence against ROS)

A
  • Superoxide dismutase (SOD)
  • This enzyme in isolation would not be enough
  • In combination with catalase both superoxide and hydrogen peroxide are neutralized
38
Q

Alternative to catalase: glutathione peroxidase (GP)

defence against ROS

A
  • Like catalase turns hydrogen peroxide into harmless water

- Oxidized glutathione (GSSG) regenerated to reduced glutathione (GSH) by glutathione reductase (GR)

39
Q

Antioxidants (defence against ROS)

A
  • Vitamins: can accept single electrons from free radicals (R.) neutralizing them
  • result is another free radical that is less reactive i.e. less damaging
  • Lowered reactivity in free radical due to the possibility of mesomeric resonance structures
  • Example: ascorbic acid (Vitamin C)
40
Q

Glutathione

A
  • tripeptide: g-glutamyl-cysteinyl-glycine
  • Dual purpose in toxicology: conjugation of electrophiles followed by conversion of the conjugates into mercapturic acids which are excreted, protection against oxidative stress
  • Conjugation results in depletion of reduced glutathione: both roles at odds with each other
41
Q

Toxicology of Carcinogenesis

A

Genotoxicants
- direct: toxic compounds interacts directly with DNA, causing mutations
- indirect: damage to proteins involved in e.g. DNA replication and repair
Other causes (mostly of a regulatory nature):
- endocrine disruptors (disrupted endocrine regulation)
- epigenetic changes (disrupted regulation of gene expression)
- peroxisome proliferators (a type of transcription factor –> disrupted regulation of gene expression)

42
Q

Necrosis

A
  • Accidental
  • Cell damage
  • Organelle swelling/disruption
  • ATP levels fall
  • Loss of plasma membrane integrity: release of intracellular contents
  • Digestion by lysosomal enzymes
  • Local inflammation (phagocytes migrate to site)
43
Q

Apoptosis

A
  • Programmed cell death = “natural” process
  • Organelles remain intact for much of the time: cell often shrinks
  • ATP levels high
  • Plasma membrane remains intact: no release of cell contents
  • Digestion by caspase enzymes
  • No inflammation (neighbouring cells ingest apoptotic bodies)
44
Q

Examples of Metabolism of Xenobiotics/Drugs

A
  • Benzo[a]pyrene metabolism and toxicity
  • Aspirin overdose
  • Paracetamol overdose

AP0510 Medical Biochemistry (21 decks)

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