3. Physiology II Flashcards
Metabolic Functions of the Liver: Carbohydrate Metabolism Summary: • Glucose buffer function: • Storage of \_\_\_\_. • \_\_\_\_.
- Conversion of other dietary sugars to ____.
- Formation of biosynthetic compounds from metabolites of the ____ metabolism.• Liver is central organ in carb metbaolism
○ Also lipid metabolism - impt steps > listed on the slide
glycogen
gluconeogenesis
glucose
carbohydrate
- Summary:
- Use of fatty acids to supply energy for other physiological functions: ____.
- Synthesis of cholesterol, phospholipids, and most lipoproteins.
- 80% of synthesized cholesterol is converted into ____.
- Synthesis of lipids from proteins and carbohydrates.• Metabolism of proteins, inc formation of urea in the urea cycle
b-oxidation
bile salts
Metabolic functions of the liver: protein metabolism
• Summary:
• Deamination of amino acids into keto-acids:
• Required for energy, conversion into lipids or
____ (gluconeogenesis).
- Formation of urea for the removal of ammonia from body fluids.
- Ammonia derives from deamination and ____ in the GI.
- Formation of plasma proteins.
- Except ____ (antibodies).
- 90% of ____ proteins.
- Amino acid interconversion and synthesis of compounds derived from amino acids.
- Biosynthesis of ALL ____.
carbohydrates bacterial metabolism gamma-globulins plasma non-essential amino acids
Detoxification Functions of the Liver: Xenobiotics Metabolism
- Xenobiotics - foreign compounds:
- Possibly ____: poisons, plant alkaloids, pharmacologic molecules (e.g. drugs).
- Usually introduced as ____: e.g. plant natural products.
• Elimination of xenobiotics: ____.
• Increase in the rate of inactivation and excretion of xenobiotics.
• Conversion from ____ molecules (easy absorption and retention in the body) to
____ molecules (excretion in the urine or bile).
• Multiple enzymes primarily in the ____.
• It can also activate xenobiotics to more ____ forms.
• It is essential in the pharmacokinetics of many ____.
- Phases:
- Phase I: Introduction of ____ groups (OH, COOH).
- Phase II: ____ (glucuronic acid, glycine, taurine, sulfate).
toxic food biotransformation lipophilic hydrophilic liver toxic drugs
polar
conjugation
Detoxification Functions of the Liver: Xenobiotics Metabolism
• Xenobiotics ○ Not part of our nutrition, \_\_\_\_ molecules ○ Obtain in diet as part of collection natural products (plants produce for own reasons> \_\_\_\_ involved in defense, \_\_\_\_ that help avoid predation) ○ Our body has always been in contact with these § Have a biological effect on our body > usually \_\_\_\_ • Evolved pathways involved in elim of XB > biotransformation ○ Tries to detoxify the bio effect of these molecules by inc rate of inactivation > efficient \_\_\_\_ of molecules OR \_\_\_\_ intermediates ○ Lipophilic molecule > easily absorbed, and cross membranes of cell > retained at high rate § Hydrophilic (converted to be more polar, or electrical charges) § Retention is then impaired > excretion through urine or bile ○ Main system involved in biotransformatino is the one in \_\_\_\_, but other organs have detox systems as well • BT pathways have evolved to protect body from natural products, but enzymes evolved to carry out function are blind > by carrying out a specific rxn that may inc hydrophilicity of a molecule > it's now more \_\_\_\_ than the original one ○ However, ability to modify molecules > making more biologically active precursors > used in \_\_\_\_ of many drugs ○ Some drugs are in inactive form, and then become \_\_\_\_ by undergoing detoxification
small
alkaloids
poisons
bad excretion inactivate liver toxic
development
activated
Xenobiotics Metabolism
____ microsomal enzymes (oxidation, conjugation)
Hepatic ____ enzymes (oxidation, conjugation)
Hepatic ____ enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase, hydrolysis, ox/red)
extrahepatic
microsomal
non-microsomal
Detoxification Functions of the Liver: Xenobiotics Metabolism
• Phase I reactions:
• ____, reduction and oxidation, exposing or
introducing a ____ group (-OH, -NH2, -SH or
–COOH).
• Increase ____.
• Slightly increase ____.
• Enzymes mostly locate in the ____ (some in
the cytoplasm, e.g. ____ detoxification).
- Phase II reactions:
- ____, sulfation, ____, methylation, conjugation with glutathione, and conjugation with amino acids (glycine, taurine and glutamic acid).
- Strongly increase ____.• Phase I
○ Series of enzymes either oxidize, reduce, hydroxylate, hydrolysis or exposing a new functional group > molecule will have inc hydrophilicity
○ Presence of -OH > more polar, less lipophilic
• Phase II
○ In general, addition of big, ____, chemical groups (as big as the introduction of AA, or monosaccharides)
§ Sulfate
§ Glucoronic acid (monosaccharide)
hydrolysis functional reactivity hydrophilicity smooth ER alcohol
glucuronidation
acetylation
hydrophilicity
bulky
Phase I Reactions: Cytochrome P450 Enzymes
• Microsomal monooxygenase cytochrome P450 enzymes:
• Oxidation/reduction enzymes.
• Most important in biotransformation due to catalytic versatility and number of xenobiotics metabolized.
• 400 isozymes in 36 families.
• ____-containing proteins: ____ ring with Fe atom.
• Abundant in ____ (microsomal vesicles).
• Biosynthesis or catabolism of steroid hormones, bile
acids, lipophilic vitamins, fatty acids and eicosanoids.
• Nomenclature: • CYP (\_\_\_\_) + \_\_\_\_ + individual \_\_\_\_: • CYP1A2: metabolizes \_\_\_\_. • CYP3A4: most \_\_\_\_ CYP with \_\_\_\_ substrate specificity. • CYP2E1: metabolizes \_\_\_\_ and ethanol.
• Most impt enzymes: CP450 enzymes ○ Located in microsomal vesicles (in the SER) ○ Contain as active site > heme w/ iron § Exactly like heme group in \_\_\_\_ and those cytochromes in the ox phos chain ○ 450 > for the \_\_\_\_ of light as which these enzymes absorb the most • CYP (gene family) > P450 enzymes; first number is a subfamily, and then the individual enzyme • Some enzymes have a wide specturm of action > can modify via ox/red a lot of subtrates; other enzymes are more restricted in their range of substrate specificity
heme pyrrole liver smooth ER gene family subfamily gene caffeine abundant broad acetaminophen
Hb
wavelength
Phase I Reactions: P450-mediated Redox Reactions
In the drug-oxidizing reaction, one atom of ____ is used to form a hydroxylated metabolite of a drug.
The hydroxylated metabolite may be the end product of the ____ or serve as an ____ that leads to the formation of another metabolite.
Mechanism of reaction:
1. Drug/metabolite substrate binds to ____ (i.e., Fe3+)
P450.
2. ____ of the drug/P450 complex by CYP reductase,
using electrons donated by the reduced form of ____.
3. The drug/reduced (i.e., Fe2+) P450 complex interacts
with ____.
4. ____ drug/metabolite and water are produced.
• Redox > will go over cycles of oxidation of reaction (themselves, substates, and cofactors) 1. Drug substrate > will bind to P450 cytochrome molecule which is in an oxidized state (iron atoms in the heme group are in the +3 balance) 2. Through redox reaction with another enzyme CP450 reductase (+flavoprotein), the CP450 will get reduced (has obtained electrons from the oxidation of NADPH to NADP+, reduced flavoprotein will now reduce the CP450) 3. Enzyme will interact with molecules of O2 > formation of complex bound to O2 4. O2 oxidizes the drug and oxidizes the CP450 back to its original form > new intermediate metabolites that in a more oxidized form i. A metabolite that's more oxidized is less \_\_\_\_
oxygen reaction intermediate oxidized reduction NADPH oxygen oxidized
lipophilic
Participation of CYP Enzymes in the Metabolism of Clinically Important Drugs
CYP Enzyme
Examples of substrates
1A1
Caffeine, Testosterone, R-Warfarin
1A2
Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6
17-Estradiol, Testosterone
2B6
Cyclophosphamide, Erythromycin, Testosterone
2C-family
Acetaminophen, Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19);
2E1
Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6
Acetaminophen, Codeine, Debrisoquine
3A4
Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R- Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine
• Wide range of substrates for \_\_\_\_ • Others are even wider in their spectrum ○ 2C does well done \_\_\_\_ • Same molecule can be modified by different enzymes ○ Modifications are different > oxred reactions, but may not be the same modifications
1A1
drugs
Phase I Reactions: P450-mediated Redox Reactions
- Mechanisms of Biotransformation:
- Formation of an inactive polar metabolite:
- ____
- Formation of an active metabolite:
- ____, caffeine
- Formation of a toxic metabolite:
- ____ – NAPQI• Enzymes are blind, will modify a molecule bc that molecule fits into their active site, and the enzymes don’t know if the product that results is going to be inactive, more active or toxic
○ 3 possibilites:
§ Formation of an inactive polar metabolite (goal of the pathway)
§ But, since the enzymes are blind > can act on metabolite to make them active
§ Or, the modification of an inactive metabolite results in a toxic product (worst case)
phenobarbital
clopidogrel
aceaminophen
P450-mediated Biotransformations: Formation of an Inactive Polar Metabolite
• Example: Phenobarbital
• Barbituric acid derivative: ____-inducing and
antiepileptic.
• Hydrophobic: penetrates the ____,
slow renal elimination.
• Excretion: 75% in the form of ____ metabolites.
• ____ not a good substrate for conjugation
reactions:
• Phase I: P450s add a polar ____ group to the aromatic ring.
• Phase II: conjugation with ____ or
sulfate.
• He wants us to get what can happen from each of these slides • Modification of phenobarbital > fits the goal of the pathway perfectly ○ Active molecule > initially modified > results in an inactive metabolite ○ \_\_\_\_ (active) > retained in the body • First reaction > highlight in red > P450 enzymes add a -OH to the original active PB metabolite (on aromatic group), the original PB is not a good substrate for the phase II enzymes > this modification makes the metabolite inactive, but more easily conjugated by phase II enzymes (add sulfate or GA)
sleep blood brain barrier conjugated phenobarbital hydroxyl (OH) glucuronic acid
hydrophobic
P450-mediated Biotransformations: Formation of an Active Metabolite
- Example: Clopidogrel (Plavix, Iscover, Clopilet, Ceruvin).
- Irreversible inhibitor of the platelet P2Y12 ADP receptor.
- Functions:
- ____ drug.
- ____ agent.
- ____ pro-drug with no pharmacological activity.
• Active metabolite:
• ____ derivative.
• Formed in the liver in two ____-mediated
steps.
• Clopidogrel ○ The active agent of plavix is not active at all ○ First must be absorbed by intestine > during absorption by intestine > clopidogrel can be the substrate for a family of enzymes > esterases § 85% of CD that is reaching the intestine is directly inactivated by the esterases > the \_\_\_\_ group is lost § 15% of the CD escapes inactivation of this step > via two sets of P450 enzymes (2C19) the end result > \_\_\_\_ metabolite (has the functions of the drug, NOT THE ONE GIVEN TO THE PATIENT) ○ Took advantages of CP450 enzymes
antiplatelet
fibrinolytic
inactive
thiol
P450
methyl
active
P450-mediated Biotransformations: Formation of a Toxic Metabolite
• Example: Acetaminophen (paracetamol).
• ____, anti-inflammatory.
• Inhibitor of cyclooxigenases (mainly ____).
• P450 metabolism in the liver forms ____ (N-acetyl-p-benzoquinone imine), an ____ agent.
• NAPQI is primarily responsible for the toxic effects
of paracetamol: acetaminophen overdose.
• Treatment with ____.
• At usual doses, NAPQI is quickly detoxified by
conjugation with ____.
• Sometimes the actions of the enzymes make things worse > formation of metabolite that's toxic • During detoxicaition > follow the blue lines ○ PA can be directly by phase II enzymes > add sulfate or GA > these metabolites are ianctive (ok) • Some CP450 enzymes can recognize the PA and then they modify in such a way > NAPQI (red path) ○ Toxic > alkylating agent > can react with macromolecules in the cell (\_\_\_\_ and \_\_\_\_ of NA > activating NA and enzymatic activities) ○ Accumulation of this > responsible for the toxic effects of PA > acetaminophen overdose ○ Only to inactive > allow \_\_\_\_ reaction > conjugation of molecule with glutathione ◦This is induced by treatment with N-acetyl-cysteine, which is a \_\_\_\_ molecule that reduces glutathione so that it can be attached
analgesic COX-2 NAPQI alkylating N-acetyl-cysteine glutathione proteins bases phase II reduced
P450s Also Metabolize Endogenous Metabolites
• CP450 enzymes are involved in many reactions that have nothing to with detox: ○ Synthesis of \_\_\_\_ ○ Synthesis of \_\_\_\_ hormones from cholesterol § Testosterone and its derivatives § Enzyme that regulated by negative feedback by bile acids in hepatocytes > cytochrome P450 enzyme Therefore, some P450 enzymes are involved in the \_\_\_\_, some are a part of the general \_\_\_\_ of the cell
FA
steroid
detoxification
metabolism
Phase II reactions: Conjugation • Phase II reactions: • Major conjugation reactions • Glucuronidation - \_\_\_\_ capacity. • Sulfation - \_\_\_\_ capacity. • Acetylation - \_\_\_\_ capacity.
- Other Conjugation Reactions: ____, S- methylation, ____ conjugation (glycine, taurine).
- Adding large chemical groups to a metabolite > conjugation reactions
high low variable O-methylation amino acid
Conjugation Reactions: Glucuronidation
• Example: Morphine.
• Morphine is conjugated to form ____.
• M6G is the major ____ metabolite of morphine.
• Responsible for pharmacological effects of morphine and ____.
• Morphine is not an active molecule ○ M6G (morphine + GA) is the active metabolite of morphine ○ Phase II conjugation reaction
morphine-6-glucuronide (M6G)
active
heroine
Conjugation Reactions: Sulfation
• Example: Minoxidil. • Trade name: Rogaine. • \_\_\_\_ channel opener. • Antihypertensive \_\_\_\_ medication. • Slows hair loss and promotes hair regrowth in patients with \_\_\_\_ (male baldness). • \_\_\_\_ is the active metabolite.
• Minoxidil > present in rogaine (anti-baldness medicine) ○ Minoxidil sulfate is the active metabolite
potassium
vasodilator
adronergic alopecia
minoxidil sulfate
