Ethanol Metabolism Flashcards
describe the major route of ethanol metabolism in your body
describe the reactions catalyzed by alcohol dehydrogenase, acetaldehyde dehydrogenase, and acetyl CoA synthetase
discuss the products of ethanol metabolism
major route of ethanol metabolism is in the liver. acetaldehyde (toxic) can go into the mito matrix for further oxidation and some can escape the liver, going into the bloodstream and causing nausea and flushing in a hangover
alcohol dehydrogenase rxn cellular location: cytosol action: oxidation of ethanol --> acetaldehyde oxidizing agent: NAD+ requires zinc (always has a 2+ charge)
acetaldehyde dehydrogenase
cellular location: mito matrix
action: oxidation of acetaldehyde –> acetate
oxidizing agent: NAD+
acetyl CoA synthetase
cellular location: mito matrix of a muscle cell
action: activates acetate by attaching a CoA to it
reactant: acetate, CoA, ATP
products: AMP + PPi + acetyl CoA
costs the cell a second ATP to turn AMP –> ADP, then ADP can b turned –> ATP again (adenylate kinase rxn)
ethanol metabolism produces a lot of NADH
the acetate produced is mostly aerobic and can be used by muscle cells (especially useful as fuel in heart muscle and skeletal muscle cells which have mitochondrial acetyl CoA synthetase)
- the acetyl CoA synthetase rxn can attach CoA to acetyl group, costs ATP
- the acetyl CoA gets oxidized further in the TCA cycle
explain how the active site of alcohol dehydrogenase uses an element in its active site
uses zinc in its active site
helps a proton be released from ethanol’s oxygen
NAD+ as oxidizing agent accepts a hydride ion from the alcohol’s carbon. this is how the aldehyde is formed
describe the other principal route in your liver for the oxidation of ethanol to acetaldehyde (i.e. - the microsomal ethanol oxidizing system, MEOS)
describe how oxidation of ethanol catalyzed by the MEOS is more damaging to the liver than oxidation of ethanol catalyzed by alcohol dehydrogenase
describe why the proportion of ethanol oxidized by the MEOS increases with an increase in the amount of ethanol ingested in a single evening
describe why the proportion of ethanol oxidized by the MEOS increases with an increased frequency of ethanol ingestion (more chronic use)
major enzyme is cytochrome p450 called CYP2E1
location: ER of the liver
cytochrome P450 enzyme associated with the ER
oxidizing agent: NADPH + O2
expected place of accidental production of superoxide ion. this makes it more dangerous than the alcohol dehydrogenase rxn.
in a moderate ethanol consumer, the MEOS is responsible for about 10-20% of ethanol oxidation and the rest is by the alcohol dehydrogenase rxn
the proportion of ethanol oxidized by the MEOS increases with the increase of ethanol digested. The alcohol dehydrogenase in the cytosol can be saturated with its substrate, ethanol, increasing the percentage of ethanol oxidized by the microsomal system (which isn’t as easily saturated)
someone who chronically consumes alcohol in excessive amounts can induce the synthesis of more CYP2E1, giving the potential for free radical damage to the liver
describe the acute effects of ethanol metabolism arising from an increased NADH/NAD+ ratio in liver cells
NADH is produced in the cytosol by the alcohol dehydrogenase rxn as well as in the mitochondrial matrix by the acetaldehyde dehydrogenase rxn.
a lot of NADH in the cytosol (from alcohol dehydrogenase rxn) forces the DHAP rxn to push the direction of making glycerol-3-P (which becomes the backbone for making triacylglycerols)
fatty acyl CoAs deliver their fatty acyl groups to glycerol backbones as glycerol-3-Ps made from DHAPs.
FA transferases catalyze the transfer of fatty acyl groups to the glycerol backbones. these are endoplasmic reticular enzymes that are inducible and can lead to being more and more present which means fat synthesis would increase
explain the development of hyperlipidemia and/or hepatic steatosis (fatty liver) upon ingestion of ethanol
fatty acids come from the following places:
- FA from a recent meal
- FA made in the liver
- the acetate made in the liver can be turned –> acetyl CoA which can be used to make fatty acids - FA from adipocytes via lipolysis
- lipolysis increases when a person ingests ethanol (because the ethanol consumption increases epinephrine in the bloodstream)
the liver cell after ethanol consumption isn’t in a place to use FA as fuel very much because of the accumulation of NADH from the acetaldehyde dehydrogenase rxn in the mito matrix which inhibits beta-oxidation. instead, the liver is in a mode to produce FAs and fats.
It wants to ship those out into VLDLs and send them into blood – this is how HYPERLIPIDEMIA occurs
the liver can be damaged o the point where it has trouble delivering VLDLs and the triacylglycerols produced after consumption of ethanol are likely to stay in thee liver and cause FATTY LIVER DISEASE
explain the development of ketoacidosis, lactic acidosis, hyperuricemia, and hypoglycemia (in the fasting state) upon ingestion of ethanol
ketoacidosis = high level of ketone bodies in the blood
- causes an overwhelm in the buffer systems and lower pH in the bloodstream
- the culprit? a lot of NADH present from the acetaldehyde dehydrogenase rxn which forces the malate dehydrogenase rxn to go the direction that uses NADH (reduction of OAa –> malate). this makes OAA hard to find when an acetyl Co is deciding to go into TCA cycle or ketogenesis. it will decide to go the ketogenesis route and produce excess ketone bodies = ketoacidosis
lactic acidosis
- pyruvates can be reduced –> lactates (lactate dehydrogenase rxn, which uses NADH). the lactate dehydrogenase rxn would use the NADH produced from the ethanol dehydrogenase rxn happening in excess
- COOH (product of the lactic dehydrogenase rxn) goes out into bloodstream causing lactic acidosis
hyperuricemia
= higher than normal level of uric acid in the blood
- lactate and urate compete for same route out of body via tubular secretion. when more lactate is available, the competition with urate makes it difficult for the body to rid urate, causing urate to crystallize and cause gout
hypoglycemia in the fasting state
think about the non-carbohydrate precursors for gluconeogenesis (lactate, glycerol, alanine):
LACTATE
- if you don’t eat during ethanol consumption, you make yourself hypoglycemic (low blood sugar level)
- because of the high NADH level due to the alcohol dehydrogenase rxn, the lactate dehydrogenase rxn goes the direction of pyruvate –> lactate vs lactate –> pyruvate
- the use of lactate to make glucose becomes impaired due to the rxn going the wrong way
ALANINE
- can become pyruvate but doesn’t get far before being turned to lactate in the lactate dehydrogenase rxn due to the NADH excess from the ethanol dehydrogenase rxn
- the pyruvate made from alanine doesn’t get to the mito matrix before being released in the cytosol to lactate
GLYCEROL
- can still become glycerol-3-P but the next step (where it gets oxidized to DHAP) doesn’t happen and it goes the other direction because there’s so much NADH from the ethanol dehydrogenase rxn
what’s the problem with dehydration and ethanol consumption
body attempts to rid lactate, urate, and ketone bodies via urination. ethanol makes it more difficult for your post. pit. gland to release antidiuretic hormone which reduces the release of these waste products
less ADH means you will urinate more and have loss of water
explain how acetaldehyde increases the free radical damage to the liver caused by consumption of ethanol
microsomal ethanol oxidizing system has the ability to produce ROS which can cause lipid peroxidation.to protect the cell from ROS damage, the cell needs a lot of reduced glutathione, but when acetaldehyde binds, it makes a schiff base adduct with glutathione and the reduced glutathione no longer works in the glutathione peroxidase rxn which protects cells from ROS damage
the glutathione peroxidase system also uses NADPH as reducing agent similar to MEOS. if there isn’t enough NADPH available, glutathione can’t be reduced for the glut. peroxidase rxn (another hit!)
what is the effect of lipid peroxidation on the cells?
describe the role of acetaldehyde in the development of ethanol induced hepatitis.
describe the effects of acetaldehyde on hepatic synthesis and secretion of plasma proteins and VLDL particles
- membrane damage & slows secretion of materials out of liver cells, causing H2O to osmotically enter the cell and cell will swell (HEPATITIS). This will cause transaminases and liver enzymes to leak out into bloodstream (a sign of liver damage)
- damage to ETC (stops using NADH as it normally would)
Describe the role of acetaldehyde in the development of ethanol induced hepatitis.
Describe the effects of acetaldehyde on hepatic synthesis and secretion of plasma proteins and VLDL particles.
Explain how acetaldehyde increases the free radical damage to the liver caused by consumption of ethanol.
Acetaldehyde causes damage via MEOS
- Generates ROS
- Lipid peroxidation damages cell membranes & other membranes inside cell
(i.e. mitochondrial membrane)
- Excessive solutes osmotically pull water into cell thru damaged membrane causing cell to swell
Test ALT & AST (liver enzymes bc they spill out of damaged liver cells & can indicate an issue)
Acetaldehyde uses NADPH & binds with:
Glutathione & diminishes its ability to protect itself against H2O2 & lipid peroxidation
Free radical defense enzymes
Cell has a harder time defending itself against ROS
AA inhibiting protein synthesis (blood proteins – clotting factors)
Microtubules inhibiting protein secretion (VLDL export too 🡪 fatty liver)
Aldehydes can react with amine groups 🡪 Schiff base adduct formation
Causes free radical damage to get worse
