Test 3: 48 and 50 Flashcards
histology of a unhealthy liver show
steatosis- accumulation of lipids in liver
progression of liver disease
hepatomegaly → steatosis → fibrosis → cirrhosis → liver failure
hepatocytes absorb toxins, chemicals, drugs and nutrients from ___ before they enter the ___
sinusoidal body
hepatic vein
hepatocytes absorb toxins, chemicals, drugs come from the ___ and ___ before entering the hepatic vein
hepatic artery
portal vein
hepatocytes excrete bile acids and waste material into canaliculi through __ side
basolateral
pathway of small molecules and drugs through liver
Class 1 enzymes (cytochrome P450, flavin monooxygenases)
hydroxylation, epoxidation, demethylation
Class II enzymes (glucuronyl transferase, glutathione S transferase, N acetylation
Made soluble by conjugation with GSH, glucuronic acid, taurine ect
excretion through urine
Class 1 enzymes in liver system
Class 1 enzymes (cytochrome P450, flavin monooxygenases)
Made more soluble either by removal of hydrophobic groups by hydroxylation, epoxidation, demethylation ect.
Class II enzymes in liver
Class II enzymes (glucuronyl transferase, glutathione S transferase, N acetylation
help make more soluble by conjugation with GSH, glucuronic acid, taurine, etc.
Class II enzymes make small molecules and drugs more ___ by ___ which leads to them being excreted through urine
soluble by conjugation with GSH, glucuronic acid, taurine, ect
pathway for large and insoluble compounds in liver
Made more soluble either by removal of hydrophobic groups (Class I enzymes) or conjugation with soluble compounds (Class II enzymes) in the liver
Emulsified in bile acids in the hepatocytes, deposited in the bile duct and excreted into the small intestine as waste
how does alcohol lead to toxicity of acetaminophen
acetaminophen = Tylenol
alcohol causes CYP 2E1
CYP2E1 will change Tylenol into N acteyl benzoquinon imine- which is a highly negative toxic compound
what are some functions of P450 monoxygenases
- activation/ inactivation of drugs: aspirin, Tylenol, warfarin
- chemical carcinogenesis: activation of xenobiotic (foreign) chemicals and carcinogens into DNA reactive forms
- Participation in physiological pathways: steroid hormone biosynthesis, cholesterol metabolism, fatty acid metabolism
p450 is a __ protein
heme
how does P450 work
cytochrome P450 reductase takes 2 electrons from NADPH and binds to FAD and FMN
cP450R gives 1 electron to p450 which reduces the heme allowing O2 to bind
The O2 gets kicked off and 1 oxygen forms water, the other oxygen used to oxidize substrate
breakdown of erythromycin
cyt P450 demethylates (takes off H3C groups)
inactivates erthromycin
excreted through bile
hepatic tissue plays a key role in the excretion of many waste products such as ___- the degradation product of the heme component of red blood cells.
bilirubin
Drugs are being taken up by the liver, degraded and excreted either through the ___ system or through___depending on the size and type.
bile duct
urine
The liver is placed strategically between the gut and the rest of our body and it acts as a ___ and prevents the passage of bacteria and other harmful by products of digestion from the gut into the blood.
filter
____ can lead to many complications including gastrointestinal hemorrhage, accumulation of water in the body, jaundice, and hepatic encephalopathy.
Hepatic cirrhosis
___ is enlargement of the liver
hepatomegaly
in end stage of liver failure, liver function is progressively compromised and the ___ are lost by apoptosis or autophagy and are replaced by fibrous tissue.
hepatocytes
Metabolic conversion of drugs and physiological compounds serves two purposes:
1) Modulating the pharmacological potency of drugs and making the compounds more polar.
2) Creating groups for conjugation to GSH, glucuronic acid, acetyl group of Acetyl CoA, and sulfate from appropriate donor compounds.
In the first pathway, small molecules are made more___ by the action of ____ enzymes metabolizing enzymes from the liver microsomes (endoplasmic reticulum). The compounds are then conjugated by ___ enzymes metabolizing enzymes. The conjugates are then excreted through urine.
polar
class I
class II
Large hydrophobic molecules are made more inert (or polar) by removal of certain groups (demethylation in the case of erythromycin) or more soluble by conjugation with glucuronic acid (in the case of bilirubin) and excreted through the ____.
hepatic biliary system
example of large hydrophobic molecules that get excreted as bile
erythromycin (an antibiotic),
vitamin A, K, & E
bilirubin
example of small molecules that get excreted as urine
aspirin, acetaminophen, alkaloids and other food additives
Cats are highly vulnerable to drug induced hepatic injury due to lack of certain ___ enzymes and also inefficient ___ system.
type I or type II
GSH regeneration
Metabolic activation of drugs and chemicals requires a specific __ isoenzyme, cytochrome P450 reductase as an __ and NADPH as the source of __.
CYP
electron donor,
electrons
In the reaction cycle, CYP ___ group gets reduced by one of the two electrons extracted from NADPH and shuttled into the CYP enzyme.
heme
Transfer of electron from NADPH to CYP causes molecular ___ to bind
oxygen
The second electron shuttled into the CYP enzyme is used for splitting molecular oxygen into two oxygen atoms. One oxygen atom is sued for ___ and the other is used to make ___.
substrate oxidation
H2O
CYP activities in the liver or tissue abundance can lead to ____
hepatic toxicity.
CYP2e1 can be inhibited by prevented by intake of ___, an organo sulfur compound, found in garlic oil and broccoli. DAS also has protective effect against inflammation, high blood pressure and oxidative stress.
diallyl sulfide (DAS)
the waste in the form of ___ produced in the liver is stored in the gall bladder and emptied in the bile duct in a hormonally regulated manner
bile acid emulsion
Biochemical basis of drug-drug interaction and how alcohol, sedatives, antibiotics and barbiturates can influence the efficacy of drugs through activation or induced expression of ___
P450 genes
Bile contains water, electrolytes and organic molecules including bile acids, cholesterol, phospholipids and bilirubin that flows through the biliary tract into the ___
small intestine
There are two fundamentally important functions of bile in all species:
1) bile acids are critical for digestion and absorption of fats and fat soluble vitamins in the small intestine.
2) many waste products are eliminated from the body by secretion into bile and elimination in feces
In species with a gallbladder (man and most domestic animals except horses and rats), further modification of ___ occurs in that organ
bile
Emulsification into ___ is a major route for eliminating cholesterol and bilirubin
bile
By forming ___ – otherwise insoluble aggregates of lipids such as fatty acids, cholesterol and monoglycerides are emulsified and solubilized.
micelles
example: (cholic acid + glycine) glycocholic acid or (cholic acid + taurine) taurocholic acid (has water hating and water loving side
Bile acids are also critical for transport and absorption of the ___vitamins.
fat-soluble
Bile acids in many species are sulfonated on the 3’ position of the sterol ring by the action of class II enzyme, ___
Sulfonyl Transferatse 2A1.
Sulfonyl Transferatse 2A1, uses 3’phospho adenosine 5’ phosphosulfate as the donor of ___ group.
sulfate
will make bile acid more soluble
The sulfonated compound is more soluble, and can be excreted to some extent through ___.
urine
micelle
bile acids will form ball with hydrophobic stuff in the center, makes it more soluble easier to get rid of
Formation of unilamellar bile acid __ with entrapped waste products
vesicles
enterohepatic circulation
Large amounts of bile acids are secreted but only relatively small quantities are lost from the body.
95% are absorbed back into blood within the ileum.
Venous blood from the ileum goes straight into the portal vein, and hence through the sinusoids of the liver.
Hepatocytes extract bile acids from sinusoidal blood.
Bile acids are then transported across the hepatocytes to be re-secreted into canaliculi.
each bile salt molecule is reused about 20 times,
liver disease can decrease recirculation
Venous blood from the ileum goes straight into the portal vein, and hence through the ___of the liver.
sinusoids
___ extract bile acids very efficiently from sinusoidal blood, and little escapes the healthy liver into systemic circulation.
Hepatocytes
Flow of bile acids from liver to intestine and kidneys
Excretion of bile acids (both sulfonated and non-sulfonated) from liver to the ___ is the primary pathway of bile movement
intestine
Significant part of the bile gets ___ in the large intestine and recirculated to the liver through the portal blood supply
de-sulfonated
Part of the bile acid pool is converted to ___ by further modification and excreted through feces
secondary bile
When bile movement through the bile ducts is impaired due to obstruction or liver pathology, significant part of sulfonated bile acids are excreted through ___
urine.
Formation of ___ in the spleen, its transport to the liver and conjugation to glucuronic acid
Bilirubin
___ is the major breakdown product of the body that results from the destruction of old red blood cells (as well as some other sources)
Bilirubin
Bilirubin is removed from the blood by the liver, chemically modified by a process called ___, secreted into the bile, passed into the intestine and to some extent reabsorbed from the intestine.
conjugation
Many different liver diseases, as well as conditions other than liver diseases (for example, increased production by enhanced red blood cell destruction), can cause the serum bilirubin concentration to be ___.
elevated
Most adult acquired liver diseases cause impairment in bilirubin secretion from ___, which causes the direct (conjugated) bilirubin to be elevated in the blood.
liver cells
In chronic liver diseases, the serum bilirubin concentration is usually ___until a significant amount of liver damage has occurred and cirrhosis is present.
In acute liver disease, the bilirubin is usually ___ relative to the severity of the acute process.
normal
increased
In bile duct obstruction, or primary bile duct damage direct bilirubin concentration in the serum goes ___ because conjugated bilirubin is put back in the general circulation.
up
Increased serum levels of indirect (unconjugated) bilirubin indicate ___ liver damage (including cirrhosis, jaundice, etc) and vastly reduced liver function. The latter usually suggests loss of hepatic enzymes.
severe
In drug induced hemolysis or in hemolytic anemia, the level of bilirubin excretion is markedly ___ such that under extreme conditions, the liver is not able to cope up with the load. The excess bilirubin then accumulates in the blood plasma and eventually gets deposited under the skin, various tissues, etc., causing jaundice
increased
___ is a hepatic disease caused by inefficient flow of bile acids through the gall bladder/bile duct into the intestine
Cholestasis
Cholestasis affects the liver function in two ways:
accumulating waste materials affect liver function.
increased accumulation of bile acids in the liver causes toxicity through multiple mechanisms inducing hepatocyte autophagy
4 causes of cholestasis
- gall bladder obstruction, gall stones
- bile duct obstruction, narrowing of bile ducts, bile tumor
- liver dysfunction, defective phase II enzyme, sulfotransfease 2A1
- genetic defects affecting the rate of bile acid synthesis
___ also called as portosystemic shunting represents abnormal vascular connections of the portal vein (which connects gastrointestinal track with the liver) with Vena Cava which carries blood to the heart.
Hepatic shunting,
Hepatic shunting essentially bypasses the liver filtration and detoxification system thereby dumping toxins, bacteria, free ammonia present in the portal blood into ____.
general circulation
Hepatic shunting can either be congenital (present at birth) or acquired later in life due to ___
hepatic diseases
hepatic shunting can be either ___ or extra hepatic.
intrahepatic (joining inside liver)
what is a common symptom of hepatic shunting?
Central nervous system signs (head pressing, circling, seizures, etc) are most common
Other abnormalities include poor body condition, small stature, anorexia, depression, lethargy, disorientation, temporary blindness, comma, vomiting, fever, etc. The biochemical features include high levels of liver enzymes in the blood, high serum bile acids, and high blood ammonia
Hepatic shunting causes ___ levels of liver enzymes in the blood, ___ serum bile acids, and ___ blood ammonia
high
why is head pressing of symptom of hepatic shunting
due to ammonia toxicity in the brain
Formation of Bilirubin in the ___, its transport to the liver and conjugation to glucuronic acid
spleen
