1- Alcohol Metabolism Flashcards
- where is alcohol metabolised?
- what are the recommend units per week for men and women?
- what is 1 unit in grams?
- what can you say about the energy content of alcohol?
- alcohol is metabolised in the liver
- 14 units /week for men AND women
- 1 unit = 8g
- alcohol has a very high energy content, higher than protein and carbs, slightly lower than fat
- outline the process of alcohol metabolism, list any intermediates and enzymes.
- what is the name of the toxic metabolite & how does it affect the liver?
Alcohol ie ethanol is oxidise by alcohol dehydrogenase to form acetylaldehyde and in this step NAD+ -> NADH also. Then acetaldehyde is converted via aldehyde dehydrogenase to acetate again converting NAD+ to NADH. This acetate is conjugated to coenzyme A to form acetyl coA. This acetyl coA then goes to Krebs or is used in fatty acid synthesis
- the intermediate acetylaldehyde is a toxic metabolite. Accumulation of it is what causes the hangover. Usually keep at low conc by aldehyde dehydrogenase as it has a low Km for it. Prolonged consumption = excess NADH and acetyl CoA which causes fatty liver and cirrhosis
Outline some metabolic responses of the body to chronic alcohol consumption.
- what drug is used for alcohol dependence and how does it work?
-causes increase in NADH and lack of NAD;
1. lack of NAD means can’t convert lactate to pyruvate, lactate in blood builds up, causes lactic acidosis & kidney’s ability to excrete Uric acid reduced so unrated crystals accumulate in tissues causing gout.
2. Lack of NAD for glycerol metabolism, deficit in gluconeogenesis, hypoglycaemia
3. Lack of NAD for fatty acid oxidation, increased TAG synthesis, fatty liver
Also, increased acetyl CoA; increased synthesis of fatty acids and ketone bodies and TAGs, fatty liver
-drug= disulfiram, inhibits aldehyde dehydrogenase therefore the toxic metabolite acetaldehyde accumulates, produces hangover symptoms
- what are free radicals?
- what are reactive oxygen species (ROS) ? Give x3 examples.
- how do they cause damage in: DNA, proteins, lipids
- an atom or molecule containing one or more unpaired electrons and is capable of existing freely.
- ROS= containing oxygen, free electrons. Eg superoxide ie O2 * (produced by addition of an electron), H2O2 (not a free radical, w Fe2+ can form free radicals, readily diffusible), OH* ( most damaging and most reactive, reacts w anything).
- dna= ROS can react w bases leading to mispairing or mutations, or react with sugar causing strand break and mutation on repair
- proteins= on backbone can cause fragmentation and protein degradation, on side chains can modify amino acids (esp disulphides bridges by taking electrons from cysteine) changing protein structure causing gain or loss of function
- lipids= OH* takes H+ from fatty acids and the lipid radical formed can react w O2 to form a lipid peroxyl radical, domino effect causing many FA to be affected, membrane integrity fails. Process is called lipid peroxidation
- what are some endogenous and exogenous sources of biological oxidants?
- give some examples of diseases oxidative stress can cause.
- endogenous= electron transport chain (electrons supplied by NADH and FADH2 for O2 can sometimes escape and react with dissolved O2 to form superoxides (O2*)), nitric acid synthases (NOS), NADPH oxidases
- exogenous= radiation, polluatants, drugs, toxins
- MS, CV diseases, Crohns, cancer
- how are NOS formed?
- what are the 3 types of NOS?
- what sorts of effects do they have in the cell?
- define respiratory burst and describe it. Name a disease associated with it.
-via enzyme nitric oxide synthase, from arg to cetrulline(NADPH and O2 -> NADP+ and H2O)
-iNOS: Inducible nitric oxide, produces high con S in phagocytes for direct toxic effects
eNOS: endothelial nitric oxide synthase, for signalling
nNOS: neuronal nitric oxide synthase, for signalling
-NO* is a signalling molecule, causes vasodilation, neurotransmission
-respiratory burst= rapid release of superoxide & H2O2 from phagocytic cells, they then destroy invading bacteria. Requires O2 and NADPH for oxidation of O2 -> O2* and enzyme NADPH oxidase
-chronic granulomatous disease, genetic, problem w NADPH oxidase, more susceptible to infections eg cellulitis, pneumonia
What are the cellular defences against oxidative stress? Describe all their mechanisms (there’s 3)
1- superoxide dismutase (converts superoxide to O2 and H2O2) and catalase (converts H2O2 to H2O and O2): 2 enzymes.
2- glutathione= reduced form is GSH (levels maintained by NADPH), oxidised by glutathione peroxidase(requires selenium) to its oxidised form GSSG to form disulphide, GSSG reduced back by glutathione reductase which transfers electrons from NADPH to -S-S- bond and in the process converts ROS H2O2 -> H2O
3- free radical scavengers= vitE protects against lipid peroxidation, vitC regenerates reduced VitE, both work by donating a H+ in a non enzymatic reaction
- give 3 conditions associated with NADPH deficiency
- briefly outline the metabolism of paracetamol
- galactosaemia: galactose accumulates therefore increased activity of Aldiss reductase converts galactose -> galactitol in the process converting NADPH to NADP. compromised ROS defences, cataracts
- G6PDH deficiency, reduced NADPH made, less protection against ROS, can’t reduce GSSG to GSH, causes haemolytic & lipid peroxidation
- Heinz bodies= dark blobs in RBCs is precipitated Hb, binds to cell altering its rigidity
- paracetamol metabolism= in the hepatocyte, at normal dose is metabolised to glucuronide or sulphate, at high dose toxic metabolite NAPQI accumulates which damages proteins, DNA, lipids. Glutathione is the defence mechanism, antidote acetylcysteine replenishes its levels to clear the NAPQI.
