Chapter 6: Biotransformation and Elimination

Question 1

What is biotransformation?

Answer 1

Biotransformation is the metabolic conversion of toxicants in the body.

Question 2

Where in the body is the main site of detoxification?

Answer 2

The liver is the main site of detoxification

Question 3

Enzymes involved are typically divided into four categories based on what they do to the target compound. What are these categories?

Answer 3

1) Hydrolysis 2) Reduction 3) Oxidation 4) Conjugation

Question 4

Biotransformation occurs generally in three stages, what are they and what happens in each stage?

Answer 4

Phase 1 - compound is modified
phase 2 - compound is conjugated
phase 3 - compound is exported out of the cell

Question 5

In phase 1 of biotransformation, the modification of the compound is often done by exposing or introducing what groups? how is this done?

Answer 5

OH (hydroxy),
-NH2(amine),
-SH (thiol),
or -COOH (carboxyl)
through: Oxidation, Reduction, Hydrolysis

Question 6

What is the most common phase 1 enzyme? what are they involved in? what is their structure and how do they work? where are they located?

Answer 6

cytochrome p450 enzymes, often called CYPs. involved in the oxidation of compounds.

Heme containing enzyme that adds oxygen molecule to a substrate (i.e., the toxicant).
Mainly in the endoplasmic reticulum of the liver. Found in at least small amounts in almost all tissues.

Question 7

Humans have how many different CYP genes?

Answer 7

57

Question 8

What is coumarin?

Answer 8

coumarin is made by plants. smells nice so used in fragrances. large amounts can be hepatotoxic

Question 9

The hydroxylation of coumarin is done with what cytochrome? What is doing to coumarin?

Answer 9

CYP2A6. It is adding an oxygen atom to the hydrogen so coumarin can no longer imbed itself into the liver because it is no hydrophilic.

Question 10

What is the expoxidation of a double bond (chlorobenze)?

Answer 10

chlorobenze is a liver toxin. detoxification proceeds through an epoxide which is then transformed into a hydroxyl group.

Question 11

Heteroatom dealkylation is an example of what?

Answer 11

An example of revealing a functional group for phase II reactions is how we process caffeine. The oxidation is on the
N-methyl group, which is then cleaved off to ‘reveal’ an –NH group.

Question 12

What does CYP2D6 do?

Answer 12

CYP2D6 demethylates (thus activates-removing CH3) codeine (which on its own is not very active) to morphine (which is).

Question 13

What part of grapefruit can inhibit pharmaceutical uptake? what CYP does it inhibit and what is the consequence?

Answer 13

Grapefruits contain a furanocoumarin called bergamottin and
dihydroxybergamottin.

These compounds inhibit some human CYP450s, especially
CYP3A4, which metabolizes many of the drugs we use. Toxicants that are metabolized by this P450 are processed slower if you’ve had a few glasses of grapefruit juice!

Question 14

What are some down drug interactions with grapefruit?

Answer 14

Known drug interactions include erythromycin, warfarin and amphetamines.

Question 15

What are the major phase 2 reactions (for this class)?

Answer 15

• Glucuronidation (uses glucuronosyltransferase)
  – Sulfonation (uses sulfotransferase)
  – Conjugation with glutathione (Glutathione-S-Transferases)
  
  • These are really important! Can make up to 10% of the proteins in the liver!

Question 16

Where do most phase 2 reactions take place? which one is the exception?

Answer 16

With the exception of glucuronosyltransferases, most Phase II
enzymes are located in the cytosol.

Question 17

How does TFM kill off sea lamprey but not other sea life?

Answer 17

TFM is detoxified in many fishes through conversion to TFM-glucuronide via Glucuronidation using a UDP enzyme (i.e., UDPGT).
– TFM-glucuronide is more hydrophilic and can be cleared from the body.
– Sea lamprey do not have the same UDPGT enzyme to do this, so TFM accumulates in their tissues to exert its toxic effects.

Question 18

What is metabolic activation?

Answer 18

When something is converted into a more reactive molecule

Question 19

What are two xenobiotics that are used to induce tumors in the lab? why is this done?

Answer 19

2-AAF and DMBA are xenobiotics that are used to induce tumors in the lab to study tumorgenesis and cancer. They must be converted into carbonium to be carcinogenic and leading to liver cancer.

Question 20

What is excretion?

Answer 20

exit of toxicants and their metabolites from a tissue (effectively the body in some cases)

Question 21

What is elimination?

Answer 21

the disappearance of a substance from the body.

Question 22

What is urinary excretion? what are the properties of the toxicants excreted via urinary excretion?

Answer 22

Toxicants are excreted into urine in the kidneys through
glomerular filtration, and passive and active transport.

Toxicants that move via filtration and are polar or in ion form are excreted in urine.

Question 23

What is the most important contribution source of toxicant to fecal excretion?

Answer 23

bile

Question 24

If we have no enzymes that can break something down, where does it go/what breaks it down?

Answer 24

it goes to the gut flora to be transformed by bacteria, tho this tends to favour reabsorption.

Question 25

What are some other routes of excretion mentioned in class?

Answer 25

Exhalation – for things that exist as gases at body temperature.

Breast Milk – Human and other animals like cows

Question 26

Describe how naproxen moves through the body.

Answer 26

1. Absorption is very quick in the GI tract when taken orally (the low pH of the stomach helps with absorption)
2. Moves through the liver first to be detoxified.
3. Bound to albumin when circulating in the blood.
4. Gets excreted by the kidneys in urine.

Question 27

What is GSH and where is it used?

Answer 27

GSH is in an important intermediate molecule used in the biotransformation of acetaminophen.

Question 28

What happens if there are low levels of GSH?

Answer 28

the reactive intermediate can form adducts with biomolecules.

Question 29

what other metabolic activities that also deplete GSH levels?

Answer 29

Ethanol consumption form adducts with biomolecules!
Any other xenobiotic that gets conjugated with glutathione

Question 30

Overdoses can be rested with what? how does it help?

Answer 30

Overdoses can be treated with N-acetyl cysteine, which replenishes glutathione levels