Flashcards in lecture 12: liver biochem Deck (43):
what are xenobiotics?
foreign chemical substances in an organism not normally produced by it
describe xenobiotic metabolism
occurs in one or two phases depending on molecule:
where does xenobiotic metabolism primarily occur? excretion?
excretion = urine, feces, breath and/or sweat
what are the cytochrome P450 enzymes
CYP = family of human heme-containing proteins that modify a wide variety of compounds
+ endogenous molecules like hormones and bile acids
where are CYP enzymes found?
smooth ER or mitochondria, and mostly in the hepatocytes
conjugation with small endogenous substances in the liver will inactivate xenobiotics and endogenous molecules and/or increase their water solubility for excretion
what is UDP-glucuronosyltransferase (UGT)?
transfers glucuronic acid to substrate
most important phase II drug conjugation system and REQ'd for bilirubin excretion
what is glutathione useful for?
exists in two forms
important for antioxidant defense and cell protection because it will scavenge reactive radicals or undergo phase II conjugation
what is APAP converted into by CYP? what is it normally detoxified by?
NAPQI = hepatotoxic!
but it gets detoxified by conjugation with glutathione
what happens with high doses of APAP?
Detox pathways are saturated so the toxic NAPQI accumulates without conjugation for excretion
what effect do APAP-derived protein products have on liver cells?
mitochondrial dysfunction, ATP depletion, cell swelling => oncotic necrosis (loss of membrane integrity and release of cytoplasmic proteins
does the body store amino acids?
what is special about the liver in regards to amino acid metabolism?
the liver is the ONLY organ with the enzyme that can metabolize all of the amino acids
what other functions does the liver have in amino acid metabolism?
convert carbon skeletons of AA's into glucose
deaminate AA's into ammonia and then make urea to get rid of body fluids via urea cycle
what factors lead to breakdown of muscle?
why is alanine important?
primary carrier of the carbon skeleton used for building block of glucose and for ammonia
what does the generation and breakdown of alanine depend on ?
alanine aminotransferase (ALT) enzyme
what do aminotransferases require as cofactors?
pyridoxal phosphate (PLP)
compare ALT and AST in terms of location in organs and cells
Alanine aminotransferase (ALT) = liver, muscle, intestine = mostly cytoplasmic
Aspartate aminotransferase (AST) = liver, muscle, kidneys, brain = cytoplasmic + mitochondrial
how are ALT and AST released?
Released into circulation upon loss of membrane integrity of producer cells
what is the non-essential amino acid that the liver synthesizes from an essential amino acid?
tyrosine from phenylalanine
when does gluconeogenesis occur?
(depletion of glycogen stores)
what is meant by hepatic glucose synthesis from amino acids?
all amino acids (except leucine and lysine) can be metabolized by the liver to either pyruvate or citric acid cycle intermediates
What happens to leucine and lysine since they cannot be converted to glucose?
form ketone bodies
where are ketone bodies formed?
mitochondria of hepatocytes
when does synthesis of ketone bodies occur?
in response to unavailability of blood glucose
can ketone bodies by used by the brain?
yes - as an alternative energy source in "starvation" mode
how is that large doses of APAP can lead to blood tests with markedly elevated liver function tests (LFTs)?
death of large number of hepatocytes is indicated by massive release of ALT and AST, denoted by increased LFT results
How is it that large doses of APAP can lead to hypoglycemia?
Loss of hepatocytes for adequate glucose synthesis under fasting conditions => hypoglycemia
what kind of plasma proteins is the liver important for synthesizing?
what are clotting factor tests good for?
clotting factor tests are excellent acute measures of hepatic synthetic function
what are characteristics of hypoalbuminemia?
impaired albumin synthesis
increased albumin loss
how can impaired albumin synthesis happen?
liver disease = impaired synthesis by liver
intestinal malabsorption = less protein in
starvation = decreased protein intake
how can increased albumin loss take place?
fecal loss due to protein-losing enteropathies
skin loss due to extensive burns and skin diseases
urinary loss due to nephrotic syndrome
what are manifestations of hypoalbuminemia?
serum albumin <3.5 g/dl
bilateral pitting w/ rapid recovery
what does slower recovery of pitting suggest?
what is albumin useful for?
only useful for assessing hepatic dysfunction in chronic liver disease
how can a patient have near-normal albumin levels despite reduced hepatic albumin synthesis?
long plasma half-life of albumin masked the loss,
so there would be no hypoalbumineria nor bilateral edema
describe catabolism of amino acids.
urea cycle = only in liver
AA's broken down into ammonia which is converted to non-toxic form called urea. Urea made in the liver is excreted in the urine
what happens to the ammonia if the intestinal lumen drops in pH?
ammonia will get converted to ammonium ion, reducing its absorption. it must then wait to get excreted by feces
excessive blood ammonia levels
what does hyperammonemia cause?