biochemistry Flashcards
what is classified as binge drinking
drinking more than 10 standard drinks in one sitting
how does alcohol lead to dehydration
interferes with pituitary gland production of ADH which would normally promote aldosterone production –> therefore loss of water and salt through urine
what are the fates of the oxygen free radicals that can be created using the p450 system
can either drift off and destroy the membrane of the ER or the DNA, or can bind to the substrate
what is haemosiderin
polymer of ferritin
what is function of the Standard Ames Assay
to check whether chemicals are mutagenic or not
treatment of Crigler-Najjar syndrome
- phototherapy (10-12 hours per day)
- liver transplant
what are the types of alcohol induced liver damage
- fatty liver
- alcoholic hepatitis
- alcoholic cirrhosis
how much of the bile salts are reabsorbed
95%
what is the function of haptoglobin
- binds to the Hb that is released from RBCs when they are haemolysed at sites remote from the spleen
what holds the Fe2+ in p450
a cysteine anchor forms a ligand to the Fe in Haem
what is a microsome
artefact of breaking SER
what is the mainstay detoxification method of p450
adds an OH group to chemicals to make them soluble and then addition of a sugar to make them even more soluble
where is the active site on p450
right next to the Haem group
regions of the brain that are affected when drinking alcohol (in order) and what does this do
cerebral cortex - impaired judgement and info processing
forebrain - memory and emotions
cerebellum - balance and movement
brainstem - breathing and circulation
function of Fe in p450
alternates between 2+ and 3+ as electrons are donated to oxygen
what are the two pathways for benzopyrene
- undergoes phase one and two reactions to become a kidney safe product
- undergoes different phase 1 reaction which then goes through p450 –> carcinogen
dioxin is p450 dependent or independent to become mutagenic
independent - mutagenic without p450
what is the colour change and the causes of the colour change of bruises
- initial: reddish as blood traped in interstitial tissue - 1-2 days: blue-purple (deoxy Hb and metHb) - 5-10 days: green/yellow (biliverdin) - 10-14 days: yellow/brown (bilirubin)
what causes Gilberts disease
decreased conjugation of bilirubin and decreased uptake in some cases
what is the main p450 involved in the metabolism of prescription drugs
CYP2D6
what two levels in the serum will show pancreatitis
serum amylase and/or serum lipase elevated
what is the correlation between p450 and steroid synthesis
lots of families of p450s are involved in conversions of steroid hormone synthesis
how do you get dioxin in the environment
by-product of chlorine bleaching of paper pulp, incerating waste plastic and pesticide/herbicide manufacture
what causes gall stones
too much free cholesterol in the bile –> precipitates as crystals = gall stones
which p450 enzyme is induced with dioxin
CYP1A1
what is the number of drinks for high risk to health per day
6+ males 4+ women
how can alcohol lead to hypoglycaemia
alcohol dehydrogenase converting alcohol to acetaldehyde produces NADH. High NADP represses gluconeogensis –> hypoglycaemia
action of phenobarbitol
acts directly on DNA to turn on response elements than turn on 2B2 and 3A1 genes that upregulate the activity of p450 50-100x
what does conjugation of bilirubin mean
adds sugars to it to make it more soluble
what two hormone are involved in the regulation of pancreatic juice release
CCK and secretin
where is bilirubin produced
in the spleen (usually) as a breakdown product of RBCs
what are bile salts made of
cholesterol derivitive with a carboxylic acid group - commonly amide linked to glycine or taurine to increase solubility
what happens to the alcohol metabolism with sustained alcohol intake
CYP2E1 induced to high levels and provides an alternative pathway = microomal ethanol oxidising system
how much alcohol is cleared per hour
0.015%
what equation does p450 typically catalyse
RH + NADPH + H+ + O2 ——-> ROH + H20 + NADP+
how does phototherapy treat Crigler-Najjar syndrom
some of the souble bonds in bilirubin isomerize cis/trans bonds from Z to E configuration ==> more soluble
what are the 2 most commonly known carcinogens that result due to p450
- benzopyrene
- aflatoxin
what positive health benefits does drinking a moderate amount of alcohol do?
lower risk of heart attack, diabetes, Alzheimer’s disease, stroke and increased longevity
what happens to the haptoglobin-Hb complex
removed by the mononuclear phagocyte system, mostly in the spleen
what causes facial flushing in some people when they drink alcohol
variant of acetaldehyde dehydrogenase enzyme –> increased circulating acetaldehyde —> general vasodilation
what considerably adds to the effects of Kwashiorkor
- aflatoxin (from food) –> finds guanine in DNA in the liver –> cant make serum albumin problem –> oedema
what will the levels of haptoglobin and hemopexin be when there is intravascular haemolytic anaemia
low haptoglobin low hemopexin
main source of aflotoxin
peanuts
how many p450 genes have been identified in all organisms, and how many families have been created from that
8000 50 families
what is the absorbance of p450
~450nm when added with CO(absorbs blue light) –> red
how does lecithin help to form micelles
removes the surface tension of the fat
what happens to TG when they are remade in the enterocyte cells
go to liver –> add Apolipoproteins –> chylomicrons/VLDLs
what is the reason for poor metabolism of codeine
CYP2D6 inactive in 5-10% of caucasians and 2% of Asians and Arabs (codeine needs to be converted to morphine by CYP2D6 to have analgesic effect)
how does erythropoietin stimulate erythropoiesis
binds to EpoR which forms a homodimer and undergoes phosphorylation by interacting with JAK2 –> induces gene expression and protein synthesis
what are the functions of the different zones of the spleen
- white pulp - contains lymphocytes and accessory cells which respond to antigens in the blood
- red pulp - system of blood vessels arranged to facilitate removal of old or damaged RBCs from the circulation by macrophages
how much of the liver must be damaged for there to be clinical signs of liver disease
60% - only 40% needed
what is the structure of bilirubin
open chain of four pyrrole rings (tetrapyrrole)
how does alcohol affect drug metabolism
- prevents drug clearance when alcohol present (competition for the cytochrome pathway)
- promotes drug clearance by elevated CYP2E1 when alcohol is not present (induced increase in this cytochrome)
major reaction of p450
hydroxylation
what is the most human enzyme deficiency causing jaundice
glucose-6-phosphate dehydrogenase deficiency
how does alcohol affect the brain
interacts with the lipid bilayer of the neurons - makes them leaky –> cant fire AP as well –> suppresses nervous system
what is the cause of Crigler-Najjar syndrome
autosomal recessive disorder when you have total or partial lack of UGT1A1 - stops conjugation of bilirubin and therefore there is high plasma levels of unconjugated bilirubin
what type of chemicals does the p450 system detoxify
all foreign chemicals with a MW less than 5000
how is haem carried in the blood
initially carried on albumin and then on hemopexin –> liver
clinical signs of alcoholism (14)
- neurological disturbances
- jaundice
- altered breath
- oesophageal varices
- feminization
- extensively scarred liver
- portal HT
- enlarged collateral vessels
- ascites
- hand tremor
- hypogonadism
- easy bruising
- muscle wasting
- infertility
how many drinks do you have to use before alcohol dehydrogenase is working at its max rate
2 drinks
what is the outcome of Crigler-Najjar syndrome is the patient is untreated
kernicterus = bilirubin in the brain
T/F? p450 is not inducible
false p450 can be induced to upregulate
why does the pancreas secrete zymogens instead of active enzymes
to stop self-digestion
what is Crigler-Najjar syndrome
unable to conjugate bile at all
what happens to conjugated bilirubin in the small intestine (2 pathways)
- bacterial proteases converts it to urobilinogen 2. converted to stercobilin –> faeces (brown colour)
which sugars does the liver conjugate bile with
taurine or glycine
what is the function of ferritin
- stored in bone marrow or liver - used for erythropoiesis in bone
two main causes of pancreatitis
alcohol abuse gallstones
what are the 3 pathways that alcohol induces free radical damage of the liver
- interferes with glutathione transport -> leading to depletion in mitochondria to prevent free radical damage
- MEOS pathway (CYP2E1) loads cells with free radicals
- alcohol promotes iron absorption - catalyst for free radical production
what are the signs of severe dependence on alcohol
tremors, anxiety, sweating and vomiting
how much bile does the human body produce per day
1 litre
what is the fate of urobilinogen made by microbiota
- 90% excreted into the faeces
- 10% reabsorbed via the portal vein: –> 1% excreted through the kidneys –> urobilin when oxidised in kidneys (yellow) –> 9% recycled back into conjugated bilirubin
which liver enzymes are increased in alcholics
GGT ALT CDT
what type of enzyme is p450
monoxygenase
how is bilirubin carried in the blood
binds serum albumin as it is highly hydrophobic
two fold inactivation of trypsinogen
peptide segment occupying active site trypsin inhibitor
pancreatic enzymes are synthesized as ……
zymogens
which cytochrome is upregulated with heavy drinking
CYP 2E1
what happens to haemoglobin when it gets to the liver
Hb is split into Haem and globin
what happens to haem in the spleen
- broken down into Fe and biliverdin by haem oxygenase
- biliverdin converted by bilivirdin reductase into bilirubin , while Fe binds apoferritin to become ferritin
what does galactosaemia do
causes hepatitic inflammation –> blocking bile canniliculi –> jaundice (elevated AST and normal ALP)
what stimulates the production of erythrocytes
erythropoietin
where are cytochrome p450 enzymes located
in the smooth ER and mitochondria (not in microsomes)
what protein level is high in the blood with haemolytic jaundice
high unconjugated bilirubin
what are the most common bile acid
cholic acid deoxycholic acid chenodeoxycholic acid
what is the cause of Dubin-Johnson syndrome
autosomal recessive disorder due to a defect in cMCOT - increases the amount of conjugated bilirubin that is in the blood
what happens to acetaldehyde once made by alcohol dehydrogenase from alcohol
converted to acetate by aldehyde dehydrogenase
how many p450 genes are identified in humans
57
where are the locations of p450 in vitro and in vivo
- in vitro - microsomes - in vivo - SER
4 actions of CCK
- release of digestive enzymes from pancreas
- release of insulin from pancreas
- gall bladder contraction –> bile
- goes to brain –> satiety
function of p450 in mitochondria
for oxidising steroids - mostly in the adrenals
how does bilirubin get out of the blood and into the bile
through cMOAT actively pumping bilirubin diglucoronide into the bile caniculi (ATP dependent)
what is the relevance of upregulating the cytochrome CYP2E1 in alcoholism
it consumes NADPH so less energy is produced
what is naltrexone
drug that is an opoid receptor antagonist - blocks release of dopamine that would be released with alcohol ingestion
what is the classification system for p450 enzymes
CYP = abbreviation of cytochrome P450 number = family letter = subfamily number = form eg. CYP2A6
why are women more affected by alcohol generally?
because females have more adipose tissue and the alcohol doesnt absorb into these cells and so more in the circulation
function of ligandin in bile formation
carrier of bilirubin in cytoplasm of hepatocyte before it is conjugated (allows it to be soluble in the cell)
what is Disulfiram (antabuse)
irreversible inhibitor of aldehyde dehydrogenase –> leads to unpleasant sensations when drinking alcohol
where is acetaldehyde dehydrogenase found
in the mitochondria of the hepatocytes
ancesterol p450 gene roles
one for steroids and one for FAs
what allows Fe3+ to reduce into Fe2+
substrate binds to Fe3+ and then NADPH provides electron
main enzyme involved in detoxification
p450 cytochrome
what causes Wernicke Korsakoff Syndrome
depletion in thiamine
why do premature infants tend to show jaundice more than term infants
- newborn liver takes time to achieve adequate levels of Ligandin and UDP-glucuronyl transferase –> so levels of bilirubin can get higher
where abouts and it what proportion is alcohol absorbed
30% in stomach 70% in gut
why does the efficicacy of treatment of Crigler-Najjar syndrome with phototherapy decrease as the patient ages
due to increased thickness of skin and body surface/weight ratio
what is the major pathway of alcohol metabolism? And what are the minor pathways
major = alcohol dehydrogenase minor = MEOS and catalase
what are the main causes of haemolysis
- external attack on red cells by pathogens (bacteria and parasites) - congenital or genetic factors
what causes the pot belly in children with Kwashiorkor disease
enlarged fatty liver low serum albumin oedema leads to fluid accumulation in the belly
what are the 3 mechanisms in which p450 can be upregulated
- activate the gene (dioxin and phenobarbital) -stabilise mRNA - protect p450 from turnover
what is the cell that removes the RBCs from the circulation
macrophages
what happens to globin in the liver
hydrolysed into amino acids
what value of bilirubin is needed for jaundice to occur
>35 micromolar (3x normal value)
what attaches p450 to the SER/mitochondrial membrane
a hydrophobic protein foot
when in benzpyrene produced
from combustion products - undergoes 2 different mechanisms –> one leads to carcinogen
how does G6PD cause jaundice
reduced production of glutathione –> RBC age reduces –> haemolytic anaemia
how do zymogens stay inactive
have a peptide segment which is part of the enzyme protein itself, occupying the active site
how does the drug Orlistat work
inhibits lipase that breaks down the TG –> fatty stools
what are Heinz bodies
precipitated Hb in RBCs
what happens to acetate (made from alcohol)
oxidised for energy (TCA cycle) or converted to fat
how does the macrophage know that its time to remove a RBC
responds to altered surface molecules on the aged RBC - exposure of phosphatidyl serine - reduced content of sialic acid anchored to glycophorin - oxidative damage - more phosphatidylserine flips to the outer side of the membrane
function of alcohol dehydrogenase
conversion of alcohol to acetaldehyde
what is the advantage of having G6PD
confers resistance to malaria
which enzymes will be elevated in the blood in someone with jaundice
ALT, AST, GGT, ALP
what is the precursor of RBCs
reticulocytes
what activates chymotrypsin
enteropeptidase on enterocytes
how is blood alcohol measured
gas chromatography
is haemolytic jaundice pre/post hepatic
pre-hepatic
function of hemopexin
recycles iron
how many electrons can p450 deal with at a time
1 - it is a monoxygenase (therefore need 2 p450 to undergo reduction and oxidation when hydroxylating a substrate)
2 major causes of neonatal jaundice
- increased haem catabolism (due to change from HbF to HbA) - immaturity of the liver in bilirubin conjugation and excretion
