Liver (1)

Question 1

what are the functions of the liver

Answer 1

Nitrogen Metabolism 
Drug metabolism 
	- Metabolism of prodrugs into active forms 
	- Ethanol metabolism 
	- CYP450enzymes 
	- Drug interactions

Question 2

where inputs to the liver

Answer 2

• From the small intestine – the hepatic portal vein

* From the circulatory system - the hepatic artery

Question 3

where doe the liver output to

Answer 3

• From the liver to
1. Hepatic vein
2. bile duct.
• Metabolic regulation –hepatocytes [mitochondria]
• Carbohydrate metabolism – short term store of glycogen
• Vitamin & mineral storage
• Lipid metabolism
• Cholesterol and bile acids (regulation and production)
• Lipoprotein regulation

Question 4

how is there Removal of bacterial products & toxins and Removal of old & damaged RBC

Answer 4

Kupffer cells (specialised macrophages, phagocytosis) 
• Found in the sinusoids of the liver 
• Deal with bacterial products and toxins from the small intestine e.g. by using reactive oxygen species. E.g O2- (superoxide anion) 
• Part of the reticuloendothelial system that remove old and damaged red blood cells.

Question 5

describe Nitrogen Metabolism from amino acids

Answer 5

Amino acids are not stored in the body
we need them in our diet. There are Essential and Non- essential amino acids
Amino acids can be recycled to make new protein
I) in the liver
II) transported in the bloodstream to e.g. muscle

Amino acids can be broken down to generate ATP.
The carbon skeletons of amino acids are degraded to produce energy.
Glucogenic amino acids Produce glucose via Gluconeogenesis (Gluconeogenesis = Synthesis of glucose from non-carbohydrate precursors)
α-ketoacids are intermediates in that process.
ketogenic amino acids can be converted into ketone bodies through ketogenesis (Lysine and leucine) and enter the TCA cycle.
Some amino acids are both glucogenic and ketogenic

Question 6

describe amino acid metabolism

Answer 6

Removal of the amine group (–NH2) from amino acids - DEAMINATION
Serine and threonine can be directly deaminated
Other amino acids go via TRANSAMINATION. The transfer of the amino group from aa(1) to the alpha keto acid (2) and vice versa

Question 7

Transamination important part of Urea cycle- describe it

Answer 7

Enzymes involved:
Transaminases or aminotransferases
¥ Transamination – interconversion of aa and α-ketoacids
¥ Deamination (oxidative or non-oxidative)
¥ Ammonia Assimilation (putting NH3 into another molecs)
e.g. alanine + a-ketoglutarate –> pyruvate + glutamate
The most common molecules involved as donor / acceptor pairs are Glutamate and α-ketoglutarate i.e. they work with many aminotransferases

Question 8

describe deanimation

Answer 8

Deamination – oxidative, hydrolytic
Deamination – removal of amino group and
replace with C O and NH3 is produced.
Glutamate +H2O + NAD+ is converted to α- ketoglutarate and NH3 produced.
Glutamate Dehydrogenase can couple transamination and deamination reactions
The common acceptor of amine group is α- ketoglutarate an intermediate of TCA cycle which becomes Glutamate.
Glutamate donates amine group in form of NH3 which enters the urea cycle.

Question 9

describe Liver Function- Detoxification

Answer 9

The main site of metabolism of drugs and environmental chemicals Metabolism of many body chemicals e.g. hormones
The enzymes involved can be quite non-specific –
Why do you think this is this an advantage for the liver / the body?
Prodrugs – inactive form of the drug. Bioavailability – oral vs i.v.? Drug:Drug interactions
Often have Lipid soluble active compounds
Often end up with Water-soluble inactive compound
Excretion OR Return to intermediary metabolism
Toxic metabolites may be produced.

Question 10

describe phase 1 of drug metabolism

Answer 10

creates or uncovers a reactive group eg -OH, -COOH, -SH by e.g. oxidation, reduction, hydrolysis
Phase 1 may produce toxic metabolite

Question 11

describe phase 2 of drug metabolism

Answer 11

adds a water-soluble group to the drug or metabolite (conjugation) e.g. addition of:
GSH - the tripeptide glutathione
Amino acid or fatty acid conjugation,
Glucuronidation (addition of glucuronic acid)

Useful in drug design, Considered in drug dose:
• Prodrugs – inactive form of the drug.
Activation of the drug occurs in the liver via the Phase I and Phase II proteins.
• How efficiently each individual does this depends on their specific enzymes. Individuals can be considered ‘fast’ or a ‘slow ‘ metabololizer

Question 12

describe alcohol and it’s effect on the body

Answer 12

A highly lipid soluble and active drug
Too much alcohol can lead to: Disinhibition, Aggression, poor co-ordination
Liver & brain damage: Body needs to metabolise ethanol to get rid of the effect

Question 13

describe Acetaminophen (Paracetamol) Metabolism at normal dose

Answer 13

metabolised to conjugates and excreted

small amount of toxic metabolite formed but mopped up by phase 2 enzymes and excreted

Question 14

describe Acetaminophen (Paracetamol) Metabolism at overdose

Answer 14

more toxic metabolite produced and phase 2 enzymes
overwhelmed
If caught early – can stop effect with glutathione or derivative (acetylcysteine)

Question 15

describe CYP450’s

Answer 15

• Over 50 known, 6 metabolise ~90% of the drugs.
• Genetic plymorphisms: in these cause large differences in their metabolic rate.
• Contribute to drug: drug interactions and effective dosages
• Can be inhibited and Induced – resulting in a change in metabolic rate of drugs which can lead to complications with increased toxicity or reduced efficacy.
• Substrate of isoenzyme 3A4 – cyclosporine / erythromycin Inhibitorsofisoenzyme3A4 -grapefruitjuice/verapamil Inducers of isoenzyme 3A4 - ritonavir / rifampin
• Substrate of isoenzyme 2D6 – codeine / tramadol Inhibitors of isoenzyme 2D6 –Quinidine / sertraline
• Due to genetic differences – meaning drug gets metabolised too quickly or not at all Be Aware: Monitor the drug levels, monitor known toxicities.