So we're going to break this up now and look at Phase II metabolism which are conjugation reactions.
So in Phase II metabolism instead of using oxidases, we're using enzymes called transferases
and like the name sounds, we are transferring small polar molecules onto a drug and we're doing it to make it more water soluble.
So oxygen is not a requirement like in the previous example.
And so, examples of these polar molecules that we like to attach. Well there's Glucoronate, we have glutathione
we have - we like to attach a sulfate or an acetate from acetic acid, sulfuric acid. whatever.
So we are transferring things on to molecules.
And we call these types of reactions a conjugation reactions.
The product as a result is called a conjugate.
So let's just draw a picture of what's going on here so you can compare it to the previous example.
So if we have a drug, we want to take this drug and form a conjugate
and so, the way we do that is we transfer a molecule on to there.
So the name of the enzyme that actually works here, instead of being a cytochrome p450 or CYP 3A4,
let's say we're going to transfer an acetyl group on to it.
Well what is the endogenous polar molecule?
And many cases, this is acetyl-CoA and we've seen acetyl-CoA before.
So let's say this is S. So this is acetyl-CoA.
Here is the acetyl group.
So I take a drug, I add acetyl-CoA to it (let me just draw that arrow there)
and the way I'm able to do this with an enzyme and this enzyme is a transferase enzyme and it's called N-acetyltransferase.
Oh and I spelled that wrong. I'm having major problems spelling these days. Acetyltransferase.
And all of these enzymes that work in this system will see the word transferase at the end of the enzyme name
and so, as a result, I get a drug. It's bound to an acetyl group and I have a CoA here as a by-product
and we've seen you know acetyltransferases work in the past.
Remember you know DNA transcription, we had the histone acetylation, we had the HAT - the Histone Acetyl Transferase.
Histone Acetylation.
And the reason I'm bringing this up is not because you need to know it for pharmacology
but it's when you can attach things, the things you've learned in the past. It helps you remember them.
And so with histone acetylation, we were attaching a acetyl group on to the histones on DNA
and the result of this was to increase gene transcription.
Where else have we seen acetyl-CoA?
Hopefully, you're scratching your noggin and saying "Oh wait, wasn't acetyl-CoA in the Krebs cycle
and we took acetyl-CoA and attached it oxaloacetate and made citrate."
So, we also have acetyl-CoA in the Krebs cycle.
The point is is that you should know, you should have a sense of how these are working.
So going back Phase I, we're using oxygen and that's a big component of it. Sometimes we see this O bound to it. I should label this.
Occasionally, we see an -OH on attached to it as well to make it more polar.
Here, we are attaching endogenous polar molecules.
So what are some examples here?
We have Glucoronidation. This is the most common Phase II process that occurs.
We also have sulfation and acetylation.
And so, before I kind of mentioned alcohol dehydrogenase was an example of a non-P450 phase I reaction,
I wanted to just give you 1 example of a phase II reaction and that's with acetaminophen or Tylenol.
So 95% of acetaminophen or Tylenol is metabolized by phase II enzymes and this is the one that forms a non-toxic metabolite.
So on the next slide, what we're going to do is just look at some of these enzymes and I want to just have an appreciation here.
You don't have to really memorize too much.
The first idea here is that the CYP 3A4 enzyme, if this was a graph, a pie chart of the amount of drugs available now that are metabolizable.
CYP 3A4 metabolizes over 50% of available drugs.
One of the other common CYP enzyme that metabolizes drugs is 2D6.
Now, CYP 2D6, we've actually mentioned in the past because it's famous for polymorphisms
and by polymorphisms, it means this enzyme can do different things depending on someone's genes.
And so, we talked about codeine, how people were rapid metabolizers right?
And they take codeine and if they have a really fast enzyme, they can take codeine, they can activate it
and form morphine at a rate faster than the average person and this can be problematic especially in children
and that's why the FDA, so this one's CYP 2D6 a rapid and they're actually called ultra rapid metabolizers
and then we have you know we have a bunch of other enzymes that you don't really need to memorize because you'll forget it in I don't know a couple months.
Phase II enzymes, now what I want you to become familiar with here is just the naming of this.
So if you see this name, you'll understand what is the name of the enzymes that do glucoronidation.
Well, the name of the enzyme here and this is responsble for most of Phase II metabolism is you'll see it maybe abbreviated as UGT
and it's actually a UDP-glucoronosyltransferase and just see the word transferase in there and glucoronosyl and you'll know that's glucoronodization.
This is actually the most common phase II reaction.
This is the same process that's occurring with breaking down red blood cells and bilirubin.
When we form conjugated bilirubin, this is what's going on.
Now we have other enzyme names. So, what is GST?
Well, GST is Glutathione-S-transferase.
As the name implies, we are transferring a glutathione onto a molecule.
And so, that process is called glutathione conjugation.
How about NAT?
You should know this one. We mentioned it last time.
This is N-acetyltransferase.
It does acetylation.
And SULT. Right, SULT. Sulfotransferase.
I just want you to get familiar with the names of the enzymes and how they work
and then we have a couple other ones here that I'm not going to mention right now.
So, hopefully, this gives you a good appreciation for the Phase I and Phase II enzymes and how this works all together.
To wrap this up, we have a couple of stop, think and repeat questions.
Just 3 here. Push pause and try to do these questions
and hopefully, I'll see you at the next video.
Make sure if you like it to give it a thumbs up. Take care.