Alcohol And Xenobiotic Metabolism In Liver

Question 1

What is a xenobiotic?

Answer 1

A xenobiotic is a chemical that is foreign to the body.

Xenobiotics are metabolized by cytochrome P450 systems in the intestinal epithelial cells and in hepatocytes

Question 2

How are drugs metabolized in in the liver?

Answer 2

Drug metabolism in the liver
can add or expose a functional group (hydroxyl group)
that makes the molecule more polar for eventual excretion by the kidneys.

Metabolism of drugs in the liver occur in two phases:
- Phase I involves cytochrome P450 isozymes.
- Phase II makes the molecules more polar and follows in many
cases phase I

but some drugs are made more water-soluble by using only phase II

Question 3

Describe Cytochrome P450 system

Answer 3

CYP reductase and CYP monooxygenase work together

Cytochrome P450 reductase needs NADPH.

Cytochrome P450 contains heme
and is a monooxygenase which often forms a hydroxyl group.

CYP inactivate specific drugs, activate pro-drugs or may convert some drugs to a toxic metabolite

Question 4

What are the Cytochromes P450 isozymes in hepatocytes?

Answer 4

Different cytochromes P450 (CYP) isozymes are found in hepatocytes

CYP3A4 represents about one third of CYP in the liver. It acts on a variety of therapeutic drugs.

CYP2E1 is specific for ethanol metabolism

Question 5

How can the activity of cytochrome P450 can be increased or eecreased by drugs or natural compounds?

Answer 5

Stimulated synthesis of CYP
Some specific drugs or molecules that are metabolized by CYP can also lead to the synthesis of the same cytochrome P450.

An example is ethanol which leads to induction of CYP 2E1. High levels of CYP 2E1 interfere with metabolism of acetaminophe

Inactivation of CYP
A natural compound found in grapefruit juice inhibits CYP 3A in intestinal epithelial cells.

A daily glass of grapefruit juice can change the metabolism of many medical drugs and can alter the adjusted blood levels

Question 6

How is acetaminophen degraded?

Answer 6

This drug is mostly conjugated with glucuronate or sulfate for excretion in urine.

30%- acetaminophen sulfate (urine)

60%- acetaminophen glucuronate (urine)

Or
CYP2E1–> NAPQI—> (+GSH)—> NAPQI-SG (urine)

Question 7

Describe toxocity of acetaminophen

Answer 7

Toxicity of Acetaminophen when leading to high NAPQI level
High intake of ethanol stimulates CYP2E1 synthesis.

Glutathione binds to NAPQI

NAPQI is toxic and binds to SH-groups of proteins:
Cell death.

The drug acetadote (N-acetyl cysteine) can be injected to prevent severe hepatic damage in patients who ingested an extremely high dose of acetaminophen

Question 8

What is ethanol?

Answer 8

• Excessive alcohol consumption is a huge public health problem.
Alcoholic drinks contain different % of ethanol:
5% beer, 12% wine and 40% hard liquor by volume.

• Ethanol is a small molecule that is highly water and lipid soluble and easily passes plasma membranes

Question 9

How does ethanol lead to relaxation?

Answer 9

Ethanol acts on the cerebral cortex and enhances the activity of GABA receptors and leads to relaxation.

Question 10

Describe ethanol uptake and hepatic metabolism

Answer 10

Ethanol is readily absorbed by passive diffusion Uptake into the blood is very efficient on an empty stomac (about 70%) and in the duodenum.

More than 90% of the ingested ethanol enters the blood and is mostly metabolized by the liver.

The metabolism differs for low or high alcohol concentration in hepatocytes.

Hepatocytes oxidize ethanol in two steps: first to acetaldehyde and then to acetate which is mostly released into the bloo

Question 11

Whaat is the significance of acetate?

Answer 11

The liver releases mostly acetate into the blood.

Skeletal muscle and heart contain acetyl CoA synthetase (ACS) and use the acetate from hepatic ethanol metabolism for their TCA cycle and energy metabolism.

Acetaldehyde is toxic for the brain, heart and other organs.

Question 12

What is the significance of alcohol dehydrogehase?

Answer 12

ADH at low alcohol levels in hepatocytes:

Ethanol is the main substrate for alcohol dehydrogenase (80%) which uses NAD+ as coenzyme and forms NADH and acetaldehyde.

Hepatic alcohol dehydrogenase has a high affinity for ethanol. Many isozymes with Km ranges of 0.05 - 4 mM are found in different individuals due to hereditary variances.

Ethanol metabolism varies from individual to individua

Question 13

When is MEOS mainly active?

Answer 13

Microsomal ethanol oxidizing system (MEOS) is mainly active at high ethanol level

MEOS in hepatocytes:

Is bound in the ER membrane and uses ethanol and
NADPH to form acetaldehyde in cytosol.

MEOS has a larger Km (11 mM) and lower affinity for
ethanol than found in alcohol dehydrogenase.
MEOS contains CYP2E1 and CYP3A4. Chronic alcohol consumption induces MEO

Question 14

How is acetaldehyde metabolized in order to prevent damage?

Answer 14

Acetaldehyde is substrate for aldehyde dehydrogenases (ALDH) which use the coenzyme NAD+ to form the non-toxic acetate.

Hepatic aldehyde DH has isoforms found in mitochondria and in cytosol.
Mitochondrial aldehyde DH-2 has a high affinity and catalyzes more than 80% of the hepatic acetaldehyde oxidation.

Cytosolic aldehyde DH-1 has a low affinity and acts mainly when cytosolic acetaldehyde accumulates.

Question 15

Explain the hereditary deficiency of mitochondrial ALDH-2

Answer 15

Mitochondrial acetaldehyde dehydrogenase ALDH-2 has a higher affinity for acetaldehyde than the cytosolic form.

A common allelic variant ALDH2*2 found in individuals
of East Asian heritage leads to a decrease degradation of acetaldehyde in mitochondria. This results in high levels of acetaldehyde even at low ethanol intake.

Asian Flush Syndrome
Acetaldehyde released into the blood leads to flushing and elevated heart rate. Very high level of acetaldehyde results in the clinical feature of nausea and vomiti

Question 16

How can high ethanol intake lead to mild hypoglycemia and lactic acidemia during fasting?

Answer 16

A high cytosolic NADH/NAD+ ratio reduces hepatic gluconeogenesis:

lack of NAD+ due to excessive ethanol degradation by ADH and ALDH.
The substrates for gluconeogenesis provided by the blood cannot be used as normally.

Glycerol is phosphorylated but cannot be used to form DHAP in cytosol. Lactate cannot be used to form pyruvate at low NAD+ and stays in the blood.

Alanine is transaminated to pyruvate which is then changed to lactate at high NADH level and is released into the blood.

Glutamine is deaminated to glutamate which is used by TCA cycle enzymes to form malate that goes into cytosol.

Malate cannot be used to form cytosolic oxaloacetate. PEP carboxykinase has less substrate.

Question 17

How can high levels of cytosolic NADH lead to TAG synthesis?

Answer 17

Free glycerol from the blood

Free fatty acids from the blood

The TAGs are released into the blood inside of VLDL which leads to temporary hypertriacylglycerolemia.

Hepatic steatosis (fatty change) is an early and common consequence of chronic alcohol intake. It results from acetaldehyde toxicity. The release of VLDL is inhibited and lipid droplets accumulate inside hepatocyte

Question 18

Describe the toxicity of acetaldehyde

Answer 18

Tubulin structures are needed for the release of VLDL and proteins into the blood.

Tubulins are damaged by acetaldehyde leading to lipid and protein accumulation in hepatocytes

Question 19

What does disulfiram do?

Answer 19

Disulfiram is also known as antabuse and inhibits aldehyde dehydrogenase

Question 20

How does disulfiram lead to high levels of acetaldehyde after ethanol consumption?

Answer 20

Ingestion of ethanol leads to 5-10 times higher acetaldehyde levels when a patient takes disulfiram.

• Alcohol (small quantity) leads to: flushing, nausea
  and other signs of a “hangover”. In the event of relapses where a patient drinks a large amount of ethanol
  this can be very dangerous and the drug is used less.

Question 21

Describe the methanol toxicity

Answer 21

Methanol is found as byproduct in some alcoholic drinks and is oxidized by alcohol dehydrogenase to the highly toxic formaldehyde inside the cells of liver, neurons and retina.

Together with formic acid it leads to mental and visual disturbance (“snowstorm vision”), metabolic acidosis and if untreated methanol poisoning can lead to blindness and death.

Question 22

How is methanol toxicity treated?

Answer 22

Alcohol dehydrogenase has a higher affinity for ethanol than for methanol and early treatment includes competitive inhibition of ADH by ethanol or the drug fomepizole.

The metabolic acidosis is treated with bicarbonate and in many patients hemodialysis is needed.

Question 23

Describe ethylene toxocity

Answer 23

Ethylene glycol is found in antifreeze which has a sweet taste. It is often ingested by children, cats and dogs.

Ethylene glycol is oxidized by alcohol dehydrogenase to the highly toxic glycoaldehyde which leads to glycolic acid. Glycolic acid is changed to oxalic acid and metabolic acidosis results. After some days the destructive calcium oxalate is formed which can lead to cerebral and renal damage, hypocalcemia and even death

Question 24

How is ethylene glycol be treated?

Answer 24

Treatmen:

1. Inhibition of alcohol dehydrogenase by fomepizole or ethanol.
2. Emptying of stomach and treatment of metabolic acidosis with calcium carbonate.
3. Admission to ICU and put on a respirator and hemodialysis if needed

Question 25

How does methanol or ethylene glycol lead to metabolic acidosus with anionic gap?

Answer 25

• The anion gap is used to diagnose acid-base disorders.
• Routinely measured are sodium, bicarbonate and chloride ions.

• Anion gap = Cations – Anions = [Na+] - ([Cl-] + [HCO3-]) Normal anion gap range from 8 - 12 mEq/L

Metabolic acidosis = pH less than 7.4 and reduced bicarbonate. (anion gap is larger than 12 mEq/L)

Metabolic acidosis results from unmeasured anions reducing the pH and from reduced levels of bicarbonate. This leads to an increase in the anion gap. Poisoning with methanol or ethylene glycol leads to excess of formic acid or glycolic acid which are nonvolatile acids

Question 25

How does methanol or ethylene glycol lead to metabolic acidosus with anionic gap?

Answer 25

• The anion gap is used to diagnose acid-base disorders.
• Routinely measured are sodium, bicarbonate and chloride ions.

• Anion gap = Cations – Anions = [Na+] - ([Cl-] + [HCO3-]) Normal anion gap range from 8 - 12 mEq/L

Metabolic acidosis = pH less than 7.4 and reduced bicarbonate. (anion gap is larger than 12 mEq/L)

Metabolic acidosis results from unmeasured anions reducing the pH and from reduced levels of bicarbonate. This leads to an increase in the anion gap. Poisoning with methanol or ethylene glycol leads to excess of formic acid or glycolic acid which are nonvolatile acids