BIOL 1840U Lecture Notes - Cytochrome P450, Coagulation, Paracetamol

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Published on 29 Jan 2013
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Liver Physiology
I. Introduction
a. Normal blood flow thru liver:
i. Portal Vein—70% blood flow, 1200ml/min; Pressure =7mmHg
ii. Hepatic Artery—30% flow, 400ml/min; Pressure=100mmHg
iii. Hepatic Vein—(outflow), 1600ml/min; Pressure = 4mmHg
b. Blood flow into liver: superior mesenteric vein, inferior mesenteric vein, splenic
vein, & gastric vein join to form portal vein
c. Pathway
i. Hepatic arterioles & portal venules merge sinusoids central vein
hepatic vein
d. Space of Disse—space between hepatocytes and endothelium of fenestrated
capillaries
e. Kupher Cells—phagocytic cells lining the vessels & protecting liver
II. Biotransformation
a. Definition—process by which the liver removes substances from the blood;
modification of substances in bloodstream so that they can be excreted by body
b. Lipophilic molecules: usually bound strongly to plasma proteins; liver makes
them hydrophilic by adding a glucuronic acid group to the lipophilic molecule;
allows for filtration & excretion by kidney
c. Net movement from blood to bile: 1) delivery, 2) net uptake from space of Disse,
3) storage, 4) biotransformation, 5) secretion across canalicular membrane into
bile duct, 6) biliary flow
III. Bilirubin Metabolism
a. Bilirubin—yellow pigment derived from breakdown of heme
b. Process
i. Old RBC’s taken up by spleen & destroyed
ii. Hemoglobin is released => heme production => converted to
unconjugated bilirubin
iii. Bilirubin binds albumin & circulates in blood as a complex
iv. Complex taken up by liver & transferred to RER
v. Conjugated bilirubin is formed by adding 3 glucuronic acid molecules
vi. Secretion via bile canaliculi (RATE LIMITING STEP—requires the most
energy)
c. Hepatitis—causes increase in circulating conjugated bilirubin since the rate
limiting step is secretion &
d. Too much conjugated bilirubin in liver => spills out into bloodstream & is filtered
by kidney => excretion of dark urine
IV. Drug Metabolism
a. Acetaminophen – example of hepatotoxicity
i. Normally conjugated and secreted into bile, but small amount is oxidized
by P450 enzyme system (=> polar & reactive metabolic products)
ii. Glutathione—inactivates reactive metabolic products (“backup system”)
but can become overwhelmed
iii. Acetaminophen OD => excessive aspirin load => hepatotoxicity
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V. Synthesis
a. Liver=major synthetic organ in body, makes most proteins that circulate in blood
b. Albumin—key for binding & transporting substances; acts as osmotic agent
c. Coagulation factors—all synthesized by liver (except for Factor VIII, which is
synthesized by endothelial cells); require Vitamin K as cofactor for synthesis
VI. Processing Nutrients
a. Zone 1—located near portal triads
i. Key for glucose release, glycogen degradation, & gluconeogenesis
b. Zone 3—located near central vein
i. Involved in glycogen synthesis & glycolysis
ii. Region where the majority of alcohol metabolism occurs
c. Alcohol
i. Must be metabolized in liver (and slightly in stomach)
ii. Yields 2 NADH per molecule EtOH (7kcal/g)
iii. Process:
1. Ethanol => Alcohol dehydrogenase => acetaldehyde + NADH
2. acetaldehyde => acetaldehyde dehydrogenase => acetate +
NADH
iv. Aldehyde accumulation => a hangover! & not feeling good
v. Antabuse—anti-alcohol drug; causes accumulation of aldehydes => huge
hangover
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