Lecture 4 Prep for Exam 1

Question 1

In what form are triglycerides stored in our body?

Answer 1

esters and glycerol

Question 2

The gallbladder is basically the _____ factory of the body

Answer 2

salt

Question 3

How do you convert something that is very lipophilic (such as cholesterol in this case) and make it very amphiphilic (such as cholic acid in this case)…

Answer 3

you make it more polar

Question 4

Amphiphiles are both polar and nonpolar…what do they help aid in?

Answer 4

They are emulsifying agents (detergents) that aid in the digestion of lipids

Question 5

Where is the main factory of proteins?

Answer 5

the liver…

Question 6

What is occuring in the liver?

Answer 6

primary bile acids synthesis…cholesterol being converted into CA or CDCA (via the enzyme CYP7A1

Question 7

After the bile acids are made in the liver, where are they stored?

Answer 7

gallbladder!…these bile acids must be ready on demand once you have something of fatty material

Question 8

How many 6-membered rings does the steroid structure have? How many 5 membered rings does it have?

Answer 8

3 “6-membered” rings and 1 “5-membered” ring

Question 9

What structure is this?

Answer 9

steriod!

Question 10

How do we make amphiphilic material from lipophilic cholesterol?

Answer 10

First the hydroxylase is put at the 7th position due to NADPH being reduced to NADP+, then two things can happen to either produce Cholic Acid or Chenodeoxycholic acid…

For Cholic Acid: the 12-alpha hydroxylase will help with attaching hydroxyl group at the 12th position, there will be a reduction of the double bond in the 6 membered ring, and there will be a side chain oxidation and cleavage

For Chenodeoxycholic acid: there will be a reduction of the double bond in the 6 membered ring and there will be a side chain oxidation and cleavage (just no 12th position -OH addition)

Question 11

explain oxidation and reduction: (in terms of gain/loss of oxygen, gain/loss of hydrogen, gain/loss of electrons)

Answer 11

Question 12

Which is more polar?

Answer 12

cholic acid

Question 13

If you want the best emulsifying agent you want them to be:

a) very lipophilic and very hydrophilic
b) very lipophilic and very hydrophilic

Answer 13

a) very lipophilic and very hydrophilic

Question 14

Someone gives you a drug and says they want you to make it more water-soluble…how would you do this?

Answer 14

more water soluble=more hydrophilic

I would then ask if it is an acid, if yes, then I will add a base

If it is a base, then I would add an acid

Altogether you are getting the ionized form which is the water soluble form! Excreted more easily

(more ionization=more charge=more polarity)

Question 15

Can you use thioesters or esters for chemical reactions?

Answer 15

Use thioesters (are less stable) and you can easily modify them…they are weaker than esters

Question 16

Which is the nucleophile in the equation?

Answer 16

the amine group

Question 17

Where does the amine attack?

Answer 17

The amine will attack the carbon of the thioester group because it is more lipophilic and will transform easily to yield the acetyl choA product

Question 18

Because of the thioester reaction with amine that we understand, what basically occurs in the reaction?

Answer 18

The CoA-SH is replaced by either Taurine or glycine…in the thioester reaction with amine essentially the S was replaced with the NH…in the case of Cholyl-CoA with addition of Taurine or Glycine to yield Taurocholic acid or glycocholic acid

Question 19

What is the main message showing us from this reaction?

Answer 19

We cannot directly react an amine with a carboxylic acid

You must take the carboxylic acid and put the acid first, activate it with acetyl coA, and then react it with the amine

Question 20

What is the pkA of the two acids?

Answer 20

about 5

Question 21

What is the pH of the stomach? What is the pH of the first part of the small intestine (the duodenum)? What about the pH of the lower part of the small intestine?

Answer 21

pH of stomach= about 2
pH of duodenum= about 4
pH of the lower part of the small intestine= about 7.4/8

Question 22

Are these molecules in their protonated or their unprotonated form?

Answer 22

Question 23

If you want these molecules to have better water solubility..you want them to be…

Answer 23

CO-! ionized=better water solubility

Question 24

Can we adjust the ionizability of these bile salts in order to make it more water soluble?

Answer 24

The answer is yes, because look at the pKa now of these primary bile acids…

Question 25

Are these molecules in their protonated or unprotonated form? Why are they better emulsifying agents for lipids?

Answer 25

These conjugated bile acids are mostly in their deprotonated form…they are more water soluble and thus, better emulsifying agents for lipids

Question 26

What does to emulsify mean?

Answer 26

the process of combining two substances that normally don’t mix well together. To emulsify fats usually means to mix them with water-based liquids and a binding substance like bile salts…Emulsify fat means that you change the environment so the fat and water molecules can mix together more easily. Typically this requires you to add a compound, known as an emulsifier, which can serve as a bridge between the fat and water molecules.

Question 27

Within the intestine, what can intestinal bacteria do to the stored bile acid groups?

Answer 27

it can partially dehydroxylate and remove glycine and taurine groups to then yield secondary bile acids: DCA (deoxycholic acid) and LCA (lithocholic acid)

Question 28

Why is the best emulsifying agent taurocholic acid and not glycocholic acid?

Answer 28

B/c it has lower pKa so it is going to be higher ionized and you’ll get polar and nonpolar

Question 29

How do you make an acid more acidic? By adding an electron withdrawing group or electron donating group?

Answer 29

by adding an electron withdrawing group

Question 30

Are primary amines considered electron donating or withdrawing?

Answer 30

Primary amines are typically considered electron donating due to the lone pair of electrons on the nitrogen atom. These electrons are available for donation to other atoms in a chemical reaction

Question 31

Are secondary and tertiary amines considered to be electron donating or withdrawing?

Answer 31

They are considered to be electron withdrawing due to the inductive effect. When the amine group takes part in resonance through its free electron pair, it donates electrons through conjugation.

Question 32

Explain the mechanism that causes primary bile acids to become secondary bile acids

Answer 32

The removal of the -OH group in the 7th position of cholic acid and chenocholic acid

Question 33

Explain enterohepatic circulation

Answer 33

Question 34

What is the best emulsifying agent? Why?

Answer 34

Best is Taurocholic acid as it has a lot of OH-‘s making it very hydrophilic

Question 35

What is the worst emulsifying agent? Why?

Answer 35

Worst is Lithocholic acid as it has no -OH’s making it very lipophilic

Question 36

How does the drug-Cholestyramine-work in regard to lowering cholesterol levels?

Answer 36

Cholestyramine is a highly charged polymer…since it is highly charged it wants to form salt-bridges/electrostatic interactions with non charged species, therefore, when a molecule like cholic acid comes near, electrostatic interactions then are formed between the two groups. These interactions bind and sequester bile acids in the gut and prevent its reabsorption and forms insoluble complexes with bile acids in the intestine (excreted with feces)

When there are less bile acids in the feces this results in the conversion of more plasma cholesterol to bile acids in the liver (lowering cholesterol levels)

***IN THE PICTURE THE CHOLESTYRAMINE INTERACTS WITH BILE SALTS IN THE LIVER AND NOT IN THE GALL BLADDER (IGNORE BLUE ARROW)

Question 37

Is this drug acidic or basic?

Answer 37

-there is no hydrogen bonding (not a hydrogen bond acceptor) and the amide is neutral (unlike if it were an amine)

acidic drug!!!

Question 38

Why do we have to have the administration of statins be separated by at least four hours after cholestyramine?

Answer 38

Both Lipitor and cholestyramine will interact with each other and both will get into the feces without getting absorbed (neither will effectively bind to bile acids)…this is due to Lipitor also being an acidic drug and then interacting with cholestyramine…therefore, not only with Lipitor but any drug that is acidic and they want to switch over to cholestyramine…they will have to wait at least 4 hours before

Question 39

How does drug toxicology occur in relation to the enterohepatic circulation?

Answer 39

Sometimes when a drug is metabolized, it will then become toxic…therefore, when the drug then is reabsorbed it will then cause damage to the liver due to it being toxic …many anticancer drugs face this issue

Question 40

What are eicosanoids?

Answer 40

signaling molecules that are synthesized by oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) (all fatty acids are 20 carbon units in length)

Question 41

What are the 3 main eicosnoids?

Answer 41

prostaglandins (PG), Leukotrienes (LT) and Thromboxanes (TX)

Question 42

unsaturated means…

Answer 42

less hydrogens (double bonds)

Question 43

saturated means…

Answer 43

more hydrogen bonds (no double bonds)