Week 3 Flashcards
(16 cards)
CO affinity for haemoglobin
- CO is a chemical asphyxiant that blocks the
transport in the blood of O2 via haemoglobin
– interfering with O2 supply - Haemoglobin is a
tetramer with 4 allosteric
binding sites for O2 - Affinity for haemoglobin: CO is ~250x O2
- Dangerous level of carboxyhaemoglobin:
at 50% of blood haemoglobin content
Effects of CO in humans
Little effect is seen with concentrations of
carboxyhaemoglobin up to
35% of total haemoglobin
* As the concentration approaches 50, this leads to:
* headache, flushing, weakness, vomiting and collapse
* Patient’s skin may appear cherry-red due to peripheral
vasodilatation and the bright-red colour of
carboxyhaemoglobin
* Still higher concentrations lead to:
* coma, intermittent convulsions and respiratory failure
CO
Hydrogen cyanide
- HCN is a chemical asphyxiant that
interferes with O2 utilisation - Nearly 90% of cellular O 2 consumption is by cytochrome c during cellular respiration in the mitochondrial electron
transport system - This electron flow involving cytochrome c
can be effectively stopped by CN- binding avidly to cytochrome a3 - This results in death due to failure to meet metabolic demands
Nitrites
Nitrites can interact with haemoglobin (Fe 2+ in haem) by oxidizing it to
methaemoglobin (now Fe3+ in haem) -> can’t bind O2
* Thus nitrites can interfere with the energy production by blocking O2 transport
* Nitrites (incl. sodium nitrite) have a beneficial use as a large % of haemoglobin can be sacrificed without danger to life, i.e.
* The ferric form of iron (Fe 3+ ) in methaemoglobin can bind cyanide, thus reducing the amount of CN- available to bind cytochrome a3 in the mitochondrial electron transport system, thereby reversing the effects of cyanide! – an example of an antagonistic interaction
Methyl alcohol uses
- Industrial solvent
- Laboratory solvent
- Adulterant to denatured ethyl alcohol
Normal transmission of nerve
impulse involves:
* Transmission of a wave of
depolarisation down the axon
* Depolarisation involves selective movement of Na+ and K + ions
across the cell membrane
* When the impulse arrives at the nerve ending there is release of a neurotransmitter
* Transmitter diffuses to a receptor
* The action of the transmitter on the receptor is terminated by passive or active (e.g. enzymatic breakdown) dissipation of the
transmitter
How are mutations caused by chemicals?
(1)DNA alterations and mutagenesis:
(a) chemical covalent reactions (DNA adducts)
- result in miss-pairing (base-pair substitution),
base-loss and error-prone repair
e.g. alkylating agents, nitrogen mustards
(b) intercalation resulting in frame shifts
e.g. acridines, some cytotoxic antibiotics*
(c) UV-induced chemical alterations e.g. thymine dimers
(2) DNA repair:
- direct reversal of DNA damage or excision repair
(mutation resulting from repair error)
(3) Aneuploidy & polyploidy:
- disruption of mitosis or meiosis, resulting in loss (aneuploidy) or duplication (polyploidy) of chromosomes
Stages of Cancer Formation (1)
Initiation
* simple irreversible mutation in individual cells from a single sub-carcinogenic dose of carcinogen “Initiator”: can only initiate cells
- a true “incomplete” carcinogen is rare
- low single doses of a complete carcinogen can initiate, but usually cannot sustain promotion stage
e.g. polycyclic aromatic hydrocarbons (PAHs),
any genotoxic agent (e.g. cytotoxic anticancer agents)
Stages of Cancer Formation (2)
Promotion of initiated cell:
* depends on continued exposure; reversible if ceases
* no direct interaction with DNA; has a threshold dose
(below which there is no effect)
* modifying factors - age, diet & hormonal influences
“Promoter” agent:
* causes expansion of initiated clones of cells
Stages of Cancer Formation (3)
Progression
* irreversible; observable neoplasms
* cells show complex alterations in genetic structure, i.e.
- deletion, recombination or irreversible changes in gene expression
- instability of chromosomal constitution (“karyotype”) -> aneuploidy
“Progressor” agent:
* converts initiated or promoted cell into a potentially malignant cell
e.g. any genotoxic agent (e.g. cytotoxic anticancer agents)
Stages of Cancer Formation (4)
“Complete carcinogen”
* induces cancer in normal cells (combination initiator/promoter/progressor) i.e. high doses of an initiating compound usually acts as a complete carcinogen
Carcinogen Classification (1)
A. DNA-reactive (genotoxic) carcinogens:
* Activation-independent organics
(alkylating agents, nitrogen mustards, epoxides)
* Activation-dependent organics
(aliphatic halides; PAH; arylamines; nitrosamines;
mycotoxins – aflatoxin AFB1; drugs – cyclophosphamide*)
* Activation-independent inorganics
(Metals - Be, Cd, Cr as chromate, Ni; metalloids - As; minerals - silica, asbestos)
Carcinogen Classification (2)
B. Non-genotoxic (epigenetic) carcinogens:
* Promoters: inhibits cell communication & contact inhibition (liver enzyme inducer hepatocarcinogens - OC pesticides, barbiturates, PCBs, PBBs, PCDDs - TCDD, saccharin)
* Endocrine modifiers: for hormone-dependent tumours
(hormones – estrogen, DES, anti-androgens;
thyroid inhibitors; gastrin-elevating inducers of gastric neuroendocrine tumours – omeprazole)
* Peroxisome proliferators: not in primates?
(plasticiser phthalate esters, DEHP;
hypolipidemic drugs – clofibrate, gemfibrozil)
Cytotoxics: constant repair of damage stimulates cell growth
(mouse forestomach - BHA;
rat nasal - chloracetanilides;
rat renal - K bromate; α2μ-globulin nephropathy inducers)
* Immunosuppressives: the immune system is the last line of defence against tumours (NK & CTLs)
(cyclosporine A; purine analogs – azathioprine
Carcinogen Classification (4)
C. Unclassified:
* Miscellaneous
(alcoholic beverages, benzene, mineral oils,
shale oils, chlorinated solvents, etc.)
Common endpoints observed in pregnancy include:
- spontaneous abortion (indicating “embryotoxicity”)
- decreased development (“fetotoxicity”)
- malformations (“teratogenicity”)
