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Flashcards in lecture 12: liver biochem Deck (43):
1

what are xenobiotics?

foreign chemical substances in an organism not normally produced by it

2

describe xenobiotic metabolism

occurs in one or two phases depending on molecule:
I: activation/modification
II: conjugation

3

where does xenobiotic metabolism primarily occur? excretion?

liver
excretion = urine, feces, breath and/or sweat

4

what are the cytochrome P450 enzymes

CYP = family of human heme-containing proteins that modify a wide variety of compounds
+ xenobiotics
+ endogenous molecules like hormones and bile acids

5

where are CYP enzymes found?

smooth ER or mitochondria, and mostly in the hepatocytes

6

describe conjugation

conjugation with small endogenous substances in the liver will inactivate xenobiotics and endogenous molecules and/or increase their water solubility for excretion

7

what is UDP-glucuronosyltransferase (UGT)?

transfers glucuronic acid to substrate

most important phase II drug conjugation system and REQ'd for bilirubin excretion

8

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

9

what is APAP converted into by CYP? what is it normally detoxified by?

NAPQI = hepatotoxic!
but it gets detoxified by conjugation with glutathione

10

what happens with high doses of APAP?

Detox pathways are saturated so the toxic NAPQI accumulates without conjugation for excretion

11

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

12

does the body store amino acids?

no

13

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

14

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

15

what factors lead to breakdown of muscle?

exercise
fasting
limited oxygen

16

why is alanine important?

primary carrier of the carbon skeleton used for building block of glucose and for ammonia

17

what does the generation and breakdown of alanine depend on ?

alanine aminotransferase (ALT) enzyme

18

what do aminotransferases require as cofactors?

pyridoxal phosphate (PLP)
vitamin B6

19

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

20

how are ALT and AST released?

Released into circulation upon loss of membrane integrity of producer cells

21

what is the non-essential amino acid that the liver synthesizes from an essential amino acid?

tyrosine from phenylalanine

22

when does gluconeogenesis occur?

(depletion of glycogen stores)
extending fasting
starvation
intense exercise

23

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

24

What happens to leucine and lysine since they cannot be converted to glucose?

form ketone bodies

25

where are ketone bodies formed?

mitochondria of hepatocytes

26

when does synthesis of ketone bodies occur?

in response to unavailability of blood glucose

27

can ketone bodies by used by the brain?

yes - as an alternative energy source in "starvation" mode

28

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

29

How is it that large doses of APAP can lead to hypoglycemia?

Loss of hepatocytes for adequate glucose synthesis under fasting conditions => hypoglycemia

30

what kind of plasma proteins is the liver important for synthesizing?

albumin
CLOTTING FACTORS

31

what are clotting factor tests good for?

clotting factor tests are excellent acute measures of hepatic synthetic function

32

what are characteristics of hypoalbuminemia?

impaired albumin synthesis
increased albumin loss

33

how can impaired albumin synthesis happen?

liver disease = impaired synthesis by liver
intestinal malabsorption = less protein in
starvation = decreased protein intake
chronic infections

34

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

35

what are manifestations of hypoalbuminemia?

serum albumin <3.5 g/dl
generalized edema
bilateral pitting w/ rapid recovery

36

what does slower recovery of pitting suggest?

cardiovascular causes

37

what is albumin useful for?

only useful for assessing hepatic dysfunction in chronic liver disease

38

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

39

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

40

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

41

define hyperammonemia

excessive blood ammonia levels

42

what does hyperammonemia cause?

hepatic encephalopathy

43

what does the liver use the TCA/citric acid cycle for?

to syntesize non-essential amino acids from intermediates of glycolysis