Liver Metabolism Flashcards
What colour is P450?
Red because of the iron protoporphyrin molecule which hemoglobin also has
Why doesn’t phototherapy work for older people?
Their skin is too thick for the light to penetrate
What is haemoglobin with Fe3+ called?
Methaemoglobin
What type of enzyme are P450?
Monoxygenase
How does a bruise appear after 5-10 days?
Greenish/yellowish - due to biliverdin
What makes conjugated bilirubin soluble?
Hydrophilic glucuronate
What is the implications of substances inducing its P450?
Can lead to the development of resistance to the drug or
Some people may be poor metabolises of a drug
How does a bruise appear after 1-2 days?
Bluish-purple/blackish
How can you treat Crigler-Najjar syndrome?
Fluorescent light therapy
Liver transplant
What is the major colourant of faeces?
Stercobilin
How does a bruise appear after 10-14 days?
Yellow-brown or light brown (bilirubin)
How do mitochondria appear when centrifuged?
A straw to red colour
What is special about CYP2D6?
It metabolising aprox. one quarter of all pharmaceuticals
What is the function of the mononuclear phagocyte system?
Destruction of old RBCs and WBCs
Formation of plasma proteins
Formation of antibody
Formation of bile pigment
What are the implications of low hemopexin?
Haemolytic anaemia
In general, how do cytochromes carry O2?
Fe2+ <> Fe3+
How are different P450 systems named?
CYP [number][letter][number]
CYP means cytochrome P450
And the latter are for family, subfamily and form respectively
How is urobilinogen made?
By the action of commensals in the gut
Which disease is aflatoxin associated with?
Kwashiorkor
What percentage of RBC turn over occurs outside the spleen?
10%
What does haem oxygenase resemble?
Globin
How long due RBCs last in the blood stream?
120 days
What does haemolytic crisis result in?
Anaemia
Jaundice
What happens to benzopyrene?
Can either be inactivated and safely secreted or
Activated into a carcinogen
What converts haem into biliverdin?
haem oxygenase
What determines whether the liver or the immune system will deal with a foreign substance?
The liver handles molecules <5000 molar mass
What is the role of Fe2/3 in the P450 cycle?
Take and pass e- to make the ROS
Why is it called the P450 system not enzyme?
Because two enzymes are required for the process to occur
How much urobilinogen is excreted through the kidney?
1%
What is a cause of haemolytic disease in newborns?
Maternal ab crossing the placenta and reacting with foetal RBCs
What is the ROS created in the P450 cycle?
Peroxide
What role does albumin play in haem metabolism?
Carries unconjugated bilirubin to the liver
What is haem first converted into?
Biliverdin
What is the mononuclear phagocyte system?
Immune cell mediated system consisting of monocytes, macrophages, and to a lesser extent T and B cells in the lymph nodes, spleen and liver.
What is the function of cMOAT?
Transport conjugated bilirubin from hepatocytes into liver canaliculi
What is commonly added to substrates?
-OH group
Where is EPO synthesized?
The kidney
What is the function of P450 reductase in the P450 cycle?
Facilitate the supply of electrons from NADPH to O
What is makes up the structure of bilirubin?
4 pyrrole rings
What are microsomes?
The *in vitro *isolated form of P450 cytochromes
What enzyme is required for the conjugation of bilirubin?
UDP glucuronyl transferase
What carries iron to the liver/bone marrow after RBC destruction?
Transferrin
How many genes for P450s have been identified?
57
What does the P in P450 stand for?
Pigment
What colour bilirubin?
Yellow
At defect in what causes Crigler-Najjar disease
UDP glucuronyl transferase
What reaction does P450 typically catalyse?
RH + NADPH + O2 + H+ > ROH + NADP+ + H2O
What happens when bilirubin is exposed to light? What are the implications of that?
Double bonds isomerize making it more soluble.
Phototherapy can be used to treat jaundice
Where does aflatoxin come from in the diet?
Aspergillus fungus on corn or peanuts
What are the 3 signs of RBC aging?
Loss of sialic acid residues from glycophorin
Phosphatidylserine flips to the other side of the membrane
Oxidative damage eg Heinz bodies
What initiates P450 reaction cycle?
A substrate binding to P450
Where does the P450 process typically occur?
Smooth ER of hepatocytes
What is the purpose of the P450 cycle?
Create a ROS next to the substrate
What happens to free haemoglobin if haptoglobin is depleted?
It is excreted in the urine
What is the function of hemopexin?
It carries free haem to the liver
How many RBCs are made per second?
2 million
What is Crigler-Najjar syndrome caused by?
Mutation causing inactivation of glucuronyltransferase
Where is bilirubin usually produced?
Spleen
How long does it take reticulocytes to mature into RBCs?
1 day
How is the lifespan of RBCs calculated?
Tagging them with radioactive chromiun
What provides the electrons in the P450 cycle?
NADPH
What is kernicterus?
Neurotoxic damage due to high levels of bilirubin in the children
Where in the spleen does RBC breakdown occur?
Red pulp
Do reticulocytes have nuclei?
No
Why are P450 types specific to certain substrates?
The binding cleft must be specific for the substrate
What percentage of the population doesn’t response to codeine?
10%
What is the problem with high levels of bilirubin in children?
It’s neurotoxic
What are the physiological consequences of haemolysis
Unconjugated hyperbilirubinaemia as the liver’s capacity to metabolise Hb is saturated
Increase stercobilin in stool and urobilinogen in urine
Reticulocytosis
How much of the circulating blood are reticulocytes?
1%
In what form is bilirubin reabsorbed in the gut for excretion through the kidneys
Urobilinogen
What are some causes of hyperbilirubinaemia
Bile duct obstruction
Severe liver failure due to cirrhosis
Dubin-Johnson syndrome
What colour is urobilinogen?
Colourless
What converts biliverdin to bilirubin?
Biliverdin reductase
Which cell breaks down senescent RBCs?
Macrophages
What do mitochondria use P450 for?
Oxidising steroids
What is Dubin-Johnson syndrome caused by?
A genetic defect in cMOAT
What is haptoglobin?
Plasma protein that binds to haemoglobin for RBCs that break down outside the spleen.
What are the two forms of bilirubin?
Conjugated (direct)
Uncojugated (indirect)
Where are P450 cytochromes located within cells?
ER
Mitochondria
What happens to the haptoglobin-haemoglobin complex?
Removed with the mononuclear phagocyte complex mostly in the spleen
Why must there be many different type of P450?
Because they are specific to different substrates
Which P450 is deficient in individuals that have difficulty converting codeine to morphine?
CYP 2D6
What is the outcome of the ROS reacting with the substrate?
-OH added most commonly
Sometimes can cause others eg epoxide
What types of molecules does albumin bind?
Hydrophobic
What is are the implications of low haptoglobin in the blood?
High levels of haemolysis is occurring
