Co-substrates Flashcards by Dee Reyes

What are Phase II Biotransformation (conjugating) enzymes?

Transferases that mainly serve a detoxification function

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What is the solubility of the reaction products of phase II Biotransformation enzymes?

more water-soluble and can be excreted via kidneys or in bile

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What type of enzyme is a phase II biotransformation (conjugating) enzyme?

Bi-substrate enzymes

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What is the enzymatic reaction of phase II biotransformation (conjugating) enzymes?

To transfer a component of the cosubstrate (or all of it) to the substrate (e.g.: phenol + UDP-glucuronic acid → phenyl glucuronide + UDP)

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True or False: Compounds cannot be directly conjugated without prior metabolism if they are Phase II enzymes

False

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What is UDPGA?

It is a nucleoside diphosphate sugar that is stable, abundant, and highly water-soluble

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What are the steps in the synthesis of UDPGA?

Step 1: UDP-glucose pyrophosphorylase and Step 2: UDP-glucose dehydrogenase

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Where are UGTs located?

Endoplasmic reticulum

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What are microsomes?

Artifactual structures derived from the endoplasmic reticulum when a tissue is homogenized

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How are microsomes useful?

They are used as model systems to study ER-based drug-metabolizing enzymes, such as CYPs and UGTs, in vitro

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How do you prepare microsomes?

Through differential centrifugation

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Why do the substrates (of UGT) have to access the active site from the cytoplasm?

Because the active site of UGT is in the lumen of the endoplasmic reticulum

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Why can’t UDPGA diffuse across the membrane?

Because UDPGA and the glucuronide products are very water soluble

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What helps facilitate the entry of UDPGA and the export of glucuronides?

Involvement of active transport proteins

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What causes UGT to exhibit latency in vitro?

The location of UGTs in the ER lumen

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What can you do to increase the activity when the enzyme activity in freshly prepared microsomes is being measured?

Disrupt the membranes with e.g. a detergent

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What is the Compartmentation theory?

Access of substrates restricted

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What is the Conformation theory?

Detergent alters protein structure

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What is the difference between animals and other species when carrying out the synthesis of one molecule of PAPs?

Other species use two separate enzymes, ATP Sulfurylase, and APS Kinase to carry out the said function. Animals only require the bifunctional enzyme PAPS Synthase to carry out both reactions that synthesize one mole of PAPS.

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What are the PAPS Synthase enzymes in vertebrates?

PAPSS1 and -S2

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What are Hepatocytes?

Ex vivo model system that is useful for studying drug metabolism

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What is the main cell type in the liver

Hepatocytes

How are hepatocytes stored?

Stored at -80°C using special freezing and thawing solutions

What happens after the thawing of hepatocytes?

Can be established in cell culture to study drug metabolism (at the level of intact cells)

Acetaminophen is the active metabolite of the aniline-based analgesic/antipyretic drugs _________ and _________

acetanilide and phenacetin

True or False: acetanilide and phenacetin are still used

False: they are both toxic and are no longer being used

What is acetaminophen?

One of the most widely used drugs and is part of 300 different OTC and prescription medicines (OTC: over-the-counter)

What does acetaminophen do?

They serve as temporary mild analgesia for headache, toothache, muscle pain, cold/flu symptoms, and menstrual symptoms

What is antipyretic?

"anti" means against and "pyretic" means feverish

True or False: Acetaminophen is considered safe at any dose

False: it is only generally considered safe at THERAPEUTIC doses

What type of administration does acetaminophen commonly use?

Oral dosing (e.g.: capsule or tablets)

What can Acetaminophen overdose result to?

Acute liver failure that often requires liver transplantation

How is acetaminophen excreted in therapeutic doses?

Excreted in urine as inert sulfate and glucuronide conjugates?

What is NAPQI?

The toxic metabolite of acetaminophen through the formation of mitochondrial protein adducts

In therapeutic doses, formation of NAPQI is _______

minimal

What happens to the products of NAPQI formation in therapeutic doses?

Conjugated with glutathione by GSTs and excreted in bile

What happens in acetaminophen overdose?

Sulfation then the glucuronidation pathways are saturated, so more is converted to NAPQI

What happens when glutathione stores get depleted by excess NAPQI?

NAPQI reacts with sulfhydryl groups on proteins, resulting in protein adduct formation

How do you treat acetaminophen overdose if the exposure was relatively recent?

Using activated charcoal to prevent the absorption of ingested acetaminophen

What is the main treatment for acetaminophen overdose?

Replenishment of depleted glutathione by administration (generally IV) of N-acetylcysteine (NAC)

Success of acetaminophen overdose treatment depends on _______________, _______________, and _______________

DTP: DOSE of acetaminophen taken, length of TIME before the treatment, and the NAC PROTOCOL

What are used as guides to the decision-making of treatment for acetaminophen overdose?

Treatment nomograms

What is N-Acetylcysteine a prodrug for?

L-cysteine, which is a component of glutathione

What does N-Acetylcysteine do?

Replenishes glutathione store and increases sulfation of acetaminophen

What are the two properties of N-Acetylcysteine?

Anti-inflammatory and antioxidant

True or False: Metabolic routes of acetaminophen metabolism are the same in children and adults

False: the metabolic routes of acetaminophen metabolism are distinctly different in children and adults (age-related difference)

True or False: Sulfation predominates over glucuronidation in premature and term infants, and in children up to 12 years old

True

CYP2E1 is __________ in early neonates but ________ to adult levels by approximately ____ years of age

not present, develops, 10

True or False: Glutathione S-transferases tend to be expressed at higher levels in adults than in the fetus and neonates

False: Glutathione S-transferases tend to be expressed at higher levels in the fetus and neonates than in adults

What is codeine?

A prodrug hat requires metabolism to activate its therapeutic effects

What does CYP2D6 do?

Metabolizes codeine to morphine

What happens in 0% activity of CYP2D6?

Codeine is ineffective but patients can still exhibit its side effects

What can be taken if codeine activity is inactive in the body?

Active morphine (for severe pain)

Draw the graph for Acetaminophen glucuronidation and explain what happens in the graph activity

Lower affinity, higher capacity