Week 1

Question 1

Types of Exposure

Answer 1

Intentional Ingestion: drugs, food additives, alcohol, tobacco
(ii) Unintentional: chronic exposure, allergic reactions, chronic toxic effects
(iii) Occupational Exposure: usually chronic inhalation
(lung disease) & skin dermatitis) exposure; acute exposure, accidents
Environmental Exposure: factory effluent (gas liquid-solid), spillages & dumping, continuous release
* exposure to surrounding population (and distant) is generally chronic; long term toxic effects of most industrial chemicals is unknown; most common agents include SO 2 , N2 O, NO2 , CO, pesticide residues
* Acute exposure (industrial accidents - Bhopal and Seveso)
(v) Accidental Poisoning: acute (usually drugs, pesticides, household products, natural poisons)
* Inhalation of fumes from fires
(vi) Intentional Poisoning: homicide, suicide

Question 2

Occurrence of toxicity depends on

Answer 2

dose, route & rate of adsorption, metabolic changes (Xenobiotic metabolism: activation or inactivation
- Metabolising enzymes are subject to: induction, inhibition, & changes with age, disease, etc.
pharmacogenomics / toxicogenomics)

Question 3

TD

Answer 3

Toxic dose

Question 4

LD

Answer 4

Lethal dose

Question 5

ED

Answer 5

Effective dose

Question 6

Therapeutic index

Answer 6

LD50/ED50

Question 7

Hormesis

Answer 7

bi-phasic response
- Low doses can stimulate to <30% of control levels
(by reducing highly-sensitive inhibitory biological processes to
release normal control process)

Question 8

Rate of absorption depends on

Answer 8

route of exposure: inhalation > oral > dermal
lipophilicity of chemical

Question 9

Can modify xenobiotic effects in at least 4 ways by forming:

Answer 9

1. An inactive metabolite from an active compound
   (terminating its bioactivity) - detoxication
2. An active metabolite from an initially inactive compound (pro-drug to drug; pro-carcinogen to ultimate carcinogen)
3. An active metabolite from an initially active compound e.g. Diazepam to Oxazepam, Aldrin to Dieldrin
4. A toxic metabolite from an initially active compound
   e.g. Sulfathiazole to Acetylsulfathiazole

Question 10

Xenobiotic Metabolism phase 1

Answer 10

catabolic (oxidation, reduction or hydrolysis)
* introduces a functional chemical group & increases polarity
* Cyt. P450 (CYP) is a major pathway for oxidation
* inducible by many factors (smoking, drinking, drugs, diet)

Compared to the parent xenobiotic, the metabolites are:
* more chemically reactive (sometimes more toxic)
(electrophiles; free radicals)
* more polar from introduction of reactive (functional) group
(e.g. hydroxyl/alcohol group, R-OH) for later conjugation
* more easily eliminated by kidney

Question 11

Biotransformation affects excretion

Answer 11

Chemical changes occurring with Phase I (oxidation, reduction, hydrolysis) typically
provides a functional group (R-OH) for conjugation in Phase II which ↑ renal excretion

Question 12

Cytochrome P450

Answer 12

Haem (iron) containing enzymes
* “P” for pink colour as reduced form has Fe2+ combines
with CO -> spectral absorption peak at 450 nm
* Superfamily of related but distinct isoenzymes (more than 70 gene families described) differing in:
- amino acid sequence
- substrate specificity (but overlapping)
- sensitivity to inhibitors and inducing agents
* 3 families involved in many drug reactions:
CYP1, CYP2, CYP3

Question 13

Xenobiotic Metabolism phase II

Answer 13

synthetic, anabolic (conjugation to glutathione
(GSH), sulfate, glucuronide, amino acids, etc.)
* conjugates a highly polar compound to greatly ↑ excretion Compared to Phase I metabolites the Phase II conjugate is:
* usually less active or inactive
* much more polar & more easily eliminated by kidney
Other protective factors:
antioxidants (Vit. E, Vit. C, sulfhydryls, e.g. GSH)
Toxic outcome depends on: Activation vs. Detoxication

Question 14

glutathione ‘GSH’

Answer 14

Major protection against
oxidants in biological
systems

Question 15

Factors Affecting Drug Metabolism

Answer 15

Polymorphisms (SNPs) - genes for Phase I (CYPs 2D6, 2C9, 2C19) & Phase II (UGT1A1, NAT2, COMT) -> poor or rapid metabolism
* Disease - organ damage will compromise metabolic functions
- many cytokines released during inflammation downregulate liver
CYP expression (except CYP2A6)
* Age - many enzyme activities are low in fetus & neonates, increase in adulthood, then decrease again with age (decreased liver size & blood flow -> declining metabolism)
* Gender - sex hormone-dependent expression of certain enzymes
involved in sex steroid synthesis & metabolism (CYP3A4, CYP19)
* Pregnancy - ↑ some Phase I (CYPs 3A4, 2D6, 2C9) & Phase II (UGT 1A4, 2B7) enzymes, BUT ↓some other CYPs (1A2, 2C19)

Question 16

NECROSIS

Answer 16

Regulation: No cellular control
Characterisation: Catastrophic
Cell shape: Swelling
Membrane: Ruptured
Organelles: Swollen
Nucleus: Karyolysis
Chromatin: Compact
(heterogenous)
DNA: Random cleavage
Energy: No ATP required

Question 17

APOPTOSIS

Answer 17

Regulation: Cellular control
Characterisation: Intended
Cell shape: Shrinkage
Membrane: Intact
Organelles: Intact
Nucleus: Fragmentation
Chromatin: Condensed
DNA: Oligonucleosomal cleavage
Energy: ATP required

Question 18

Type of Toxic Interaction

Answer 18

Additivity, Antagonism, Potentiation, Synergism