Alcohol and Xenobiotic Metabolism Flashcards
Function of the liver related to drug and xenobiotic metabolism
Detoxify xenobiotics and to increase their water solubility for release in urine.
Drugs are either activated or inactivated by the liver
Phase I - Hydroxylation by Cytochrome P450 (requires Heme, NADPH, and O2
Phase II - UDP-glucuronic acid for conjugation, PAPS for sulfation, and also a molecule of glutathione and or amino acids for covalent linkage to the xenobiotic.
CYP3A4
Cytochome P450 enzyme that acts primarily on therapeutic drugs
CYP2E1
Cytochome P450 enzyme that acts primarily on ethanol
Part of phase I metabolism
NAPQI
Toxic byproduct of acetaminophen metabolism in the liver.
High amounts of acetaminophen results in increased phase I metabolism by CYP2E1 which produces NAPQI. Glutathione linkae allows excretion however at elevated levels (>10%) this is not sufficient and results in severe liver damage
Treatment for acetaminophen poisoning
N-acetyl-cysteine (acetadote).
Binds NAPQI making it more water soluble for excretion
Statins and excessive grapefruit juice and Tamoxifen
Statins are metabolized by CYP3A4. Grapefruit juice inhibits this enzyme. Higher levels of statins can cause liver damage.
Tamoxifen used in breast cancer treatment reduces CYP450 resulting in less effective drug.
Ethanol absorption and degradation
EtOH is absorbed in the stomach (more on an empty stomach) and in the duodenum
Hepatocytes degrade EtOH to acetate that can be used by other tissues (muscle for energy metabolism)
[Acetate is activated to acetyl CoA by acetyl CoA synthetase]
Steps of EtOH degradation
- EtOH to acetaldehyde via hepatic alcohol dehydrogenase, needs NAD+ as cofactor
- Acetaldehyde to acetate via acetaldehyde dehydrogenase needs NAD+ as cofacor
(moderate alcohol consumption)
MEOS System
microsomal ethanol oxidizing system
Chronic ethanol consumption leads to induction of CYP2E1 for EtOH degradation (less affinity, higher Km than ADH)
Requires NADPH
generates cytosolic acetaldehyde
Alcohol Dehydrogenase (ADH)
Converts ethanol to acetaldehyde. requires NAD+ as a cofactor
Acetaldehyde dehydrogenase (ALDH)
Acetaldehyde to acetate, needs NAD+ as cofacor
ALDH 1 found in cytosol - Higher Km
ALDH 2 in mitochondria - Lower Km
Biochemical results of high EtOH consumption
Degratation of EtOH consumes 2 NAD+ resulting in high cellular NADH
Low NAD+ inhibits:
-conversion of lactate to pyruvate
High cellular NADH pushed pyruvate to lactate both resulting in lactic acidosis
- Formation of OAA from Malate and pushes OAA to Malate
- Formation of DHAP from glycerol phosphresults in hypoglycemia
Can lead to Ketoacidosis, Hypoglycemia, Lactic acidemia and Gout, hyperlipidemia, fatty steatosis
Disulfiram
Antabuse
Inhibits Aldehyde dehydrogenase
treatment for alcoholism as the drug causes flushing, nausea and are meant to prevent alcohol consumption
Produces dangerous levels of *Acetaldehyde if EtOH is consumed.
*inhibits release of proteins, including blood clotting factors
Methanol or Ethylene Glycol poisoning
Methanol leads to formaldehyde which can result in blindness in severe cases.
Ethylene glycol leads to Glycoaldehyde that can lead to toxic calcium oxalate and result in kidney failure.
Alcohol or Fomepizole are used as treatments
Effects of Phenobarbital
3-4 fold increase of CYP. Stimulates synthesis of CYP P450 therefore stimulating Heme synthesis (prothsetic group of CYP 450).
increased degradation of warfarin
Should not be given to individuals with Acute Intermittent Porphyria
