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BCHM302 Ian

Terms in this set (175)

DNA that is ________ is much more vulnerable than ________ DNA in terms of mutation.
unravelled, chromosomal
The cell membrane offers the cell ________.
protection
Toxicants can sit in the membrane and alter its fluidity, for example...
the banned insecticide DDT (dichlorophenyltrichloroethane)
DDT ________ the fluidity of the membrane
decreases
By trapping DDT in the membrane it is effectively ________ (defence mechanism)
immobilised
The structure of DDT is...
Cl3C-C(chlorophenyl)2
DDT is highly ________, making is soluble in ________.
apolar/hydrophobic, the mitochondrial membrane
One compound that blocks the TCA cycle is...
1080 (monofluoroacetic acid)
The structure of 1080 is...
This resembles ________, a molecule that enters into the TCA cycle.
CH2F-COO-
acetate
1080 forms ________ instead of acetyl-CoA, and thus ________ instead of citrate.
fluoroacetyl-CoA, fluorocitrate
Fluorocitrate is a ________ inhibitor of the enzyme ________, which converts ________ to ________ to ________ in the TCA cycle.
irreversible, aconitase, citrate to aconitate to isocitrate
1080 is absorbed across the ________ and is an ________ toxicant. Requires high dose.
gut, acute
Toxicants can also target DNA. One example of a base-mimicking toxicant is...
the anti-cancer drug 5-fluorouracil (5-FU), which is used particularly for colon cancer
5-FU is a ________ inhibitor of ________.
reversible, thymadylate synthase
Thymadylate synthase catalyses the conversion of ________ to ________.
Thus it only targets cells that are...
The cells will die because...
dUMP (uracil nucleotide) to dTMP (thymine nucleotide)

...undergoing division
...DNA replication cannot occur when no thymine is available.
Certain toxicants target protein synthesis.
Examples of this are...
antibiotics such as chloramphenicol, erythromycin, tetracyclines and streptomycin
These antibiotics target the ________ and affect it's function in various ways.
ribosome
One specific example is ________ which works by...
kirromycin; binds to the mRNA binding cleft of the ribosome
The cell defends itself from toxins in two main ways:
1) Cell membrane
2) Xenobiotic metabolism
Usually toxins must enter the cell to have a toxic effect. An exception to this is the toxin ________
tetrodotoxin
Tetrodotoxin acts by binding to the ________ on the outside of the cell.
sodium channel
There are two potentially threatening general types of molecule: ________ and ________.
Usually ________ molecules will pose a greater threat
exogenous (external toxicants) and endogenous (products of metabolism)
exogenous
Protective mechanisms have evolved to protect cells from ________ molecules, not ________ molecules; fortunately, there is some overlap between how these species are metabolised, allowing the cell to deal with external toxicants.
endogenous, not exogenous
Generally, toxic chemicals taken up by cells are ________.
hydrophobic.
The main purpose of xenobiotic metabolism is to increase their ________
water-solubility
In doing so, these molecules are more easily ________, as the majority of excretory fluids in the body are ________ (urine, sweat etc)
excreted, water-based
There are two phases of xenobiotic metabolism:
Phase 1 = ________
Phase 2 = ________
oxidation
conjugation
The oxidation of xenobiotics is carried out by ________. This involves adding on a ________.
cytochromes P450
hydroxyl group (it is possible for compounds to enter straight into the conjugation phase if they have a hydroxyl group already)
For example, benzene is oxidised to ________, which is ________
phenol, still toxic but more water-soluble
The conjugation phase involves the addition of a highly ________ group, such as ________
polar, sulfate
For example, phenol is oxidised to ________, which is ________.
phenyl sulfate, non-toxic and highly water-soluble
Overview of phase I metabolism:
Cytochromes P450 are ________ oxidases, which means...
mixed function oxidases

...they catalyse the oxidation of a range of molecules with different functional groups (have a number of different active sites)
CYP is a membrane protein that is found at particularly high concentrations in...
the ER of liver cells (as this is where most toxicant metabolism occurs)
The CYP active site contains a ________.
CYP effectively transfers ________ from an ________ molecule coordinated to this group to the substrate.
heme group

electrons, oxygen
The expression of CYP is up-regulated by ________
the substrate (toxicants)
CYP acts on both ________ and ________ substrates
aliphatic and aromatic
An example of an aliphatic oxidation carried out by CYP is the conversion of ________ to ________.
An example of an aromatic oxidation is the conversion of ________ to ________.
hexane to hexanol

benzene to phenol
Eg. metabolism of toluene:
The structure of toluene is...
benzene with a methyl group
Toluene is oxidised to form a ________.
This is further oxidised to produce ________ and ________.
This is an example of ________ oxidation.
hydroxymethylbenzene intermediate
phenol and formaldehyde (HCOH)

aliphatic
Eg. metabolism of aniline:
The structure of aniline is...
benzene with an ammonium group
Aniline undergoes oxidative deamination by CYP to form ________ and ________.
phenol and ammonia.
CYPs evolved for "natural", non-xenobiotic metabolism.
For example...
steroidogenesis (aromatase catalyses the conversion of testosterone to estradiol
Overview of the metabolism of benzo[a]pyrene:
The structure of benzo[a]pyrene is...
It is produced via the combustion of...
...five conjugated benzene rings
...organic matter
The first step of oxidation of benzo[a]pyrene produces a toxic ________ that ________ DNA and causes mutation (carcinogenic).
This is an example of where the CYP metabolism of a xenobiotic compound actually generates a more highly toxic compound.
epoxide, intercalates
Benzo[a]pyrene is a ________.
Benzo[a]pyrene epoxides are ________.
procarcinogen
carcinogens
Describe the different possible pathways for CYP metabolism of propylbenzene... (four possible outcomes; which will be the major excretory product?)
look at slides
Overview of phase II metabolism:
Four main compounds that can be conjugated to toxicants to enable their excretion are...
1) Glucuronic acid (via glucuronyltransferase)
2) Sulfuric acid (via sulfotransferase)
3) Glycine
4) Glutathione
1) Glucuronic acid:
Conjugates with phenol (alcohol) to form ________.
Conjugates with benzoic acid (carboxylic acid) to form ________.
ether glucuronide (-O- linkage)
ester glucuronide (-O-C=O- linkage)
2) Sulfuric acid:
Conjugates with phenol to form ________
phenyl sulfate (highly water soluble)
3) Glycine:
Glycine only conjugates with molecules that have ________.
Glycine binds via its ________ group.
carboxyl groups

amino
4) Glutathione:
Glutathione is a tripeptide of...
glutamate, glycine and cysteine
The glutamate forms a gamma glutamyl group because...
it forms an amide bond with cysteine via the side chain carboxyl group rather than the alpha-carbon carboxyl group
Glutathione conjugates through the ________ atom of ________.
GSH + toxicant -> ________
sulfur, cysteine

GS-toxicant
However glutathione conjugates are not excreted as this would be wasteful. Instead, they break down to form ________ which is excreted instead (in urine).
Mercapturic acid (an acetyl cysteine conjugate)
For example, glutathione will conjugate chlorobenzene to form ________
phenylglutathione
Whether a toxicant is excreted via urine or via bile/faeces depends on...
its molecular weight
Paracetamol is is metabolised to four different molecules...
quinoneimine, a sulfate conjugate, a glucuronide conjugate and a mercapturic acid conjugate
Paracetamol enters straight into phase __ metabolism because...
phase II because it has a hydroxyl group
The major metabolites of paracetamol in humans are the ________ and ________ conjugates.
________ is only produced when the pathway is completely overloaded (i.e. overdose)
sulfate and glucuronide

quinoneimine
The quinoneimine is highly toxic to the ________ as this is where the paracetamol is first metabolised. It is a highly reactive molecule that binds to ________ and ________.
liver (causes liver failure)
proteins and DNA
Paracetamol is fatally toxic to cats because...
they only have the pathway that leads to formation of quinoneimine, so even a small dose will kill them.
Aspirin does not have a toxic metabolite but high doses of aspirin are toxic because...
...it is inherently toxic
Aspirin is a prodrug for...
salicylic acid
The acetyl group of aspirin is removed in the ________ to produce salicylic acid.
stomach (due to high acidity)
The main metabolite of aspirin in humans is the ________ conjugate, followed by the ________ and ________ conjugates.
glycine, glucuronic acid and sulfate
The second role of glutathione is as an ________
antioxidant ("mops up" free radicals etc)
Glutathione exists in two forms:
Glutathione (GSH) is oxidised to ________
glutathione disulfide (GSSG)
The enzyme ________ regenerates GSH from GSSG
glutathione reductase
Because glutathione is used as a conjugating molecule, if the cell is exposed to high amounts of a toxicant, less glutathione will be available as an antioxidant. This means that the cell will be subject to more damage by free radicals.
In this way, methyl bromide (fumigant) and chlorobenzene (from paint) are ________
indirect carcinogens
Methyl bromide reacts with glutathione to produce ________
methyl glutathione
Enterohepatic circulation is the process whereby...

This is only relevant to oral drugs/toxins (not intravenous drugs) because...
...toxins and drugs are excreted via the bile and then reabsorbed in the small intestine
...intravenous drugs enter directly into the bloodstream (bypass the liver)
Acute toxicity results from... and the effect occurs...
Chronic toxicity results from... and the effect occurs...
a single dose, within a short time
multiple doses over a long period of time, after long-term exposure
The four pharmacokinetic factors that influence how toxic a particular dose is are...
1) its absorption
2) its distribution around the body
3) the speed of its metabolism
4) how quickly it is excreted
All of these relate to the substance's half life. Substances with short half lives are USUALLY ________ toxic than those with longer half lives.
less
A compound will have a different toxicity depending on its mode of ________
absorption
Four different modes of absorption are...


Describe the plot of plasma drug conc. vs time for these different modes.
The area under the curve is equivalent to...
1) Intravenous
2) Via gut
3) Intramuscular
4) Cutaneous

...the dose
Lead is toxic because it can move through the ________ channel.
Once inside the cell, it inhibits the enzyme aminolevulinic acid synthetase which is involved in the production of ________.
calcium



hemoglobin
The acute effects of lead poisoning are ________.
The chronic effects of lead poisoning are ________.
anemia
neurotoxicity
The banded krait produces a toxin called ________.
This inhibits both ________ and ________ (by mimicking ________)
alpha-bungarotoxin (a protein)
acetylcholine esterase and the acetylcholine receptor, acetylcholine
Overall, this inhibits ________.
neurotransmission
The symptoms of a krait bite are... (3)
local numbness, flaccid paralysis and death
A classic example of a substance with acute toxicity is ________
cyanide
Cyanide inhibits ________ and thus shuts down the electron transport chain and causes cell asphyxiation.
complex IV
Carcinogenesis is a type of ________ toxicity.
chronic
The two stages of carcinogenesis are...
1) Initiation (interaction with DNA)
2) Promotion (stimulation of DNA replication and cell growth)
When a molecule acts as both an initiator and a promoter this is particularly dangerous (e.g. ________)
asbestos
Higher rates of lung cancer in the UK are observed around areas where there are many ________.
The ________ from these mines is likely acting as a promotor.
coal mines, siliceous dust
The three main processes by which carcinogens function...
1) bind to DNA bases, causing the cell to recognise it as another base
2) bind to DNA bases and initiate a repair mechanism that goes wrong
3) insert into DNA and initiate repair or cause misreading
An example of a non-genotoxic carcinogen is ________.
A non-genotoxic carcinogen is a ________ but not a ________.
mustard gas (doesn't alter DNA, just increases the frequency of DNA replication)
carcinogen but not a mutagen
Mustard gas is an alkylating agent that either ________ or ________.
binds a single strand or crosslinks DNA
Crosslinking prevents ________ which leads to ________ of the tissues.
DNA replication, necrosis
Also, it is likely to be ________ that actually cause damage to DNA
errors in DNA repair
In its own right, increased DNA replication leads to an increased risk of ________
carcinogenesis
An anti-cancer drug that is based on the structure of mustard gas is ________. It forms inter- and intrastrand crosslinks that prevent ________.
cyclophosphamide, DNA replication
Cyclophosphamide is a prodrug that is converted by CYP450s to form the active metabolite ________.
The CYPs that activate cyclophosphamide are present in ________ cells, so it is used to treat these cancers.
hydroxy cyclophosphamide

lung and testicular
Pro-carcinogens are usually metabolised to carcinogens by ________
cytochromes P450
Toxicity of a compound differs between both different ________ and different ________.
tissues, species
An example of this is the chemical ________ which is used to produce azo dyes (also found in cigarettes)
naphthylamine
It is carcinogenic because it ________ DNA.
intercalates
If naphthylamine is taken up by the liver...

If naphthylamine is taken up by the kidney...
...it can be glucuronidated (detoxified) and excreted in the bile
...the carcinogen is passed on to the bladder unmodified (kidney cannot form glucuronide conjugates); leads to bladder cancer
Methyl iodide (CH3I) is converted to ________, which attaches to DNA bases, altering their structures.
the methylium cation (CH3+)
For example, methylguanine (modified guanine) has structural analogy to ________
thymine
Molecular mimicry:
In cannabis, the compound ________ is metabolised via the addition of a hydroxyl group to form the active metabolite.
tetrahyrocannibinol (THC)
THC binds to the ________ receptor in the brain, which is involved in ________.
Synthetic cannabinoids are structural analogs of THC; they bind very well to this receptor and thus have extreme side effects.
anandamide, happiness
Oestrogen mimics:
Four large-scale changes that are thought to be due to increases in environmental oestrogen mimics...
1) Girls starting puberty earlier
2) Decreasing sperm count
3) Alligators having less testosterone and smaller penises
4) Male to female oyster ratio is decreasing
17-B-estradiol is produced in ________ and ________ cells.
liver and ovary
Estradiol is taken up across the membrane of a cell and binds to a ________ in the ________. This causes a conformational change in the receptor allowing it to form a ________ which binds DNA. This leads to ________ of genes associated with feminization.
receptor, nucleus, dimer, upregulation
Estradiol and testosterone have very similar structures, however their respective receptors are highly ________
selective/specific
The key difference between estradiol and testosterone is the group on the bottom ring: in testosterone this is a ________ and in estradiol this is a ________.
These are also in slightly different positions due to the spacial arrangement of the adjacent ring (________ in testosterone and ________ in estradiol)
aldehyde (C=O), hydroxyl


hexane in testosterone, phenol in estradiol
When bound to the receptor, 17-B-estradiol interacts with three amino acids:
ARG and GLU (with a water molecule H-bonded in between) and HIS
Xenoestrogens have an effect on ________, ________ and ________ but not women of child-bearing age.
Pre-pubertal girls (they have oestrogen receptors but no oestrogen is being produced)
Post-menopausal women and men both have very constant oestrogen levels; any change is a big change.
Three 17-B-estradiol mimics are...
1) Bisphenol a
2) Genistein
3) 4-Nonylphenol
Bisphenol a (BPA) is the monomer of ________
polycarbonic plastics
When bound to the receptor, BPA forms H-bonds to ________ and ________, but not ________.
However, it is thought that the electronegativity is enough to cause the necessary conformational change.
This does mean that the interaction is less powerful than oestrogen.
ARG and GLU, not HIS
One major use of BPA is in ________
the linings of tin cans - monomers can leach out of the plastic over time
Genistein is present in ________. This contributes a significant amount to NZer's exposure to xenoestrogens.
soy
4-nonylphenol is found in ________
cleaning products
It is ________ to it's active (mimicking) form which folds to resemble oestrogen.
hydroxylated
Toxicant cocktails:
In pregnancy, the placenta functions as a barrier and has a very active ________ for the removal of toxicants.
phase II metabolism
It has been shown that oestrogen mimics (such as ________ and ________) are able to move across the placenta.
________ seems to have an unbarred movement across the placenta.
________ has a more similar structure to 17-B-estradiol so this is possibly better filtered/removed by the placenta.
Unwanted estradiol or estradiol mimics taken up by the baby upsets the development of ________.
BPA and genistein


BPA

Genistein



male genitalia
Four strange additive risk factors for increased incidence of feline thyroid cancer are...
1) Drinking from farm puddles
2) Eating canned fish
3) Living indoors
4) Sleeping on the floor or in cat hammocks
________ is a hormone made in the thyroid that binds to the thyroid hormone receptor.
The molecule has ________ atoms that are very important for its recognition.
thyroxin (T4)

iodine (halogen)
The chemical A PCB relates to the risk factor ________ because...
fish as cat food, it is an environmental contaminant found at particularly high levels in fatty fish
Erythrosine relates to the risk factor ________ because...
fish as cat food, it is a dye used to colour pink cat food
BPA relates to the risk factor ________ because...
tinned cat food, it is used to line tin cans
TBBPA relates to the risk factor ________ because...
sleeping on carpets or in cat hammocks, it is a flame retardant used in carpets and cat hammocks (absorbed through skin)
Pyrethroid relates to the risk factor ________ because...
drinking out of farm puddles, it is an insecticide used on many farms
Neural networks are connected by ________, which use neurotransmitters (such as ________ and ________) to communicate.
synapses, dopamine and seratonin
Key structural parts of dopamine: (2)
Phenol OH and aliphatic NH2 (need to have correct separation)
Key structural parts of serotonin: (4)
Phenol OH, aliphatic NH2, double ring and ring N
Key structural parts of acetylcholine: (3)
Positively charged N with methyl groups attached and a keto group at the other end
Amphetamine is a ________ analog that binds ________
dopamine, dopamine receptor
Hydroxyimipramine is a ________ analog that binds the ________, thus increasing its concentration in the synapse.
A general name for this type of drug is ________
serotonin, serotonin transporter

serotonin re-uptake inhibitor
Muscarine is an ________ analog that binds the ________.
This causes tetanic paralysis and loss of control of autonomic neural system (crying, dribbling)
acetylcholine, post-synaptic acetylcholine receptor
Psylocybin from magic mushrooms is a ________ mimic.
serotonin
Tyramine from chocolate, cheese and soy sauce is a ________ and ________ mimic.
An imbalance of serotonin and dopamine is associated with ________. Serotonin and dopamine mimics (such as imipramine and propanolol) are used to treat migraine.
noradrenaline and dopamine


migraine
ADHD is treated with the ________ mimic Ritalin
dopamine
Asbestos:
Used as a fire retardant in ________ and released when buildings are demolished.
concrete
The three forms of asbestos are blue crocidolite, brown grunerite and white crysotile.
The most toxic is ________
The most common is ________
blue crocidolite
white crysotile
The movement of the lungs while breathing causes them to contact the lining of the ________. This requires lubrication produced by the ________ cells on the lung surface.
thoracic cavity, mesothelial
Alveoli are ________ in width, meaning that the threshold for respirable particles is ________.
10-20 micrometers
5-10 micrometers
The mesothelial cells make up the stiff ________ membrane that lines the lungs. Because these cells are being constantly sloughed off by breathing, they ________ frequently.
In this way, they are primed to become ________.
pleural, divide, cancer cells
Cells in the alveoli take up asbestos fibres via ________ and it is thought that they are passed from cell to cell until they reach the ________
phagocytosis, mesothelial cells
Asbestosis as a promoter:
Asbestosis is a lung function disorder caused by ________ and is characterised by the presence of ________ in the mesothelial cells (an attempt to detoxify them). This is an inflammatory response.
inhaling asbestos, iron-coated asbestos fibres
Asbestos as an initiator:
If these fibres enter into the ________ of a cell, they up-regulate the gene encoding ________, which is involved in regulation of ________. This leads to increased cell division.
nucleus, p53, the cell cycle
81% of mesothelioma sufferers are ________ (likely to be due to exposure in the workplace). The risk of cancer increases greatly with multiple/extended exposure.
men
Asbestos use in NZ reached its peak in 1974, and the incidence of mesothelioma peaked in the 90's, meaning that there is a 15 year ________ between exposure and disease occurrence.
lag period
Asbestos has a relatively short lag period; this is likely because...
it is both the initiator and the promoter
Based on studies carried out on asbestos levels after the twin towers explosion, there will be 0.13 extra cases of mesothelioma per year after the Canterbury earthquake. This study did not look at the ________ in Christchurch though.
peak exposure
Toxicity testing and risk assessment:
Involves weighing up risk and benefit from allowing the use of a particular chemical.
...
Campylobacteriosis causes death via ________.
uncooked chicken
Paracelsus said...
The dose makes the poison
Eg: Aspirin
The risk is...
The benefit is...
...can overdose on 30 tablets
...powerful painkiller
Risk = ________ x ________
hazard x exposure
Hazard relates to...
Exposure relates to...
...the intrinsic toxicity of a chemical
...the dose
Risk perception (by the general public) can increase (e.g. ________) or decrease (e.g. ________) the weight of a risk
food (usually over-emphasised)
smoking (may convince themselves that it's not a big risk)
Eg: Fugu fish
Risk is...
Benefit is...
...dying (tetrodotoxin)
...social standing
Six methods for assessing the hazard of a chemical are...
1) SARs
2) Looking at its metabolism in the body
3) Its acute toxicity (single dose)
4) Its sub-acute toxicity (dose every day for 90 days)
5) Its chronic (lifetime) toxicity; is it carcinogenic
6) Mutagenicity assays
SARs stands for ________; this compares...
structure activity relationships, the structure of the chemical to that of one with a know toxicological effect
The EC50 is...
The effective concentration (environmental concentration that has an effect) for 50% of the population
The LD50 is...
the lethal dose (direct) for 50% of the population
LD50s have been banned, however data from old experiments is still used.
The LC50 is...
the lethal concentration for 50% of the population
NEL is...
the no effect level
NOEL is...
the no observable effect level (legal change; some unobservable changes may occur)
NOAEL is...
the no observable adverse effect level (the measure used now)
NOAEL is determined by defining an end point (e.g. ________) and then dosing the animal until the end point is reached.
change in liver enzyme concentration
Benzidine is used to test for ________ but is itself a carcinogen
colon cancer (by testing for blood in faeces)
The Ames test is used to determine whether a chemical is a ________. A positive test indicates that the chemical may be ________.
It is also known as...
mutagen, carcinogenic


...the Salmonella typhimurium His- test
The chemical is given to a colony of His- mutants, which are not able to ________ (they are grown with a very small amount of ________ to allow for growth of a "lawn").
If the chemical is a mutagen it can revert the His- mutants to His+ (the histidine locus is a hotspot for mutation), which ________
synthesise histidine, histidine





are able to synthesise histidine
One of the only cases that would pass a drug that has a positive result for the Ames test would be in the development of...
anti-cancer drugs
Examples of test systems used are...
mice, rats, dogs, rabbits, isolated cells
MSG (________) is a flavouring agent used particularly in Asian cooking.
monosodiumglutamate
MSG and glutamate ________ cross the placenta.
Its effects/uses in the body are... (3)
don't
1) Energy source in intestinal cells
2) Converted to other amino acids
3) decarboxylated to produce GABA (a neurotransmitter)
Chinese restaurant syndrome is an idiosyncratic response that has symptoms such as
red blotchy skin, shakiness, irritability, vomiting
The main difference between getting glutamate from protein in the diet and getting it from MSG is...
...glutamate from protein is released slowly during the step-by-step breakdown (no massive change in body levels of glutamate), whereas MSG delivers glutamate monomers all at once to the liver (likely has a greater effect on the GABA receptor)
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