All right friends welcome back.
So what we want to do now is understand pharmacogenomics and something called enzymatic polymorphisms
and what we're going to do is use Asian flush or the alcohol induced flush as our example
to illustrate how differences in people's genes can cause adverse drug reactions.
So the Asian flush is not actually a result of alcohol itself but it's a result of alcohol metabolism
and we see the process right here.
So alcohol actually is eventually metabolized into carbon dioxide and water but on its way to forming carbon dioxide and water,
it forms this toxic intermediate acetaldehyde and so, this bad boy is toxic
and acetaldehyde then is eventually broken down into something called acetate
but if acetaldehyde builds up, if the levels increase, this can cause the Asian flush
and we see the Asian flush right here.
So here's a picture of before someone or an Asian person drinks and after an Asian person drinks
and what we see is they've got some redness in their forehead, in their face, in their cheeks, in their neck,
they might even have a little bit of itching. Their heart rate sometimes goes up. They might even have some nausea.
We get the adverse effects from alcohol and this is all due to the acetaldehyde.
And so, our patient here is asking us, "Hey doc, why is this happening to me but not to my Asian wife?
or why does this happen to some people and not to others?"
And so the answer to this question really gets us into pharmacogenomics.
And so, if I was going to answer this question what would I say?
Well I would say, "Different people have slightly different genes and these different genes will code for different enzymes which metabolize drugs including alcohol
and because the enzymes you have are different than the enzyme your wife has to metabolize alcohol,
you are going to get a different response to alcohol.
And that is the gist of pharmacogenomics.
Now I want to say that pharmacogenomics is really connecting how different genes lead to different drug responses
and it's not just limited to different enzymes but enzymes and genes coding for them is the most studied component of pharmacogenomics
and our goal is to develop a test to look at people genes to be able to predict drug responses before they occur.
So what we want to do now is look at the enzymes involved in alcohol metabolism.
So the first enzyme that is involved is something called alcohol dehydrogenase and that is abbreviated with ADH.
Alcohol Dehydrogenase
And so, what alcohol dehydrogenase is doing is it's taking ethanol which just looks like that and you don't have to memorize these structures
and it's a dehydrogenase. So, it's stealing a hydrogen. It's oxidizing alcohol and it's forming acetaldehyde.
And we can see that we have this more polar carbon there and that's what metabolism does.
It makes things more polar.
And actually in a previous video, we taught you that alcohol dehydrogenase was a Phase I metabolizing enzyme
or this is in the Phase I reaction and that's because it's adding or unmasking a polar oxygen group.
The second enzyme involved here is acetaldehyde dehydrogenase
and I'm going to write that as ALDH-2 and we call this acetaldehyde dehydrogenase-2 and we can see that right here as well
and so, this is also a dehydrogenase. It's taking acetaldehyde and it's oxidizing it and what we're forming is acetic acid
and we know acetic acid. This is what makes vinegar sour and we can actually make this acetate as an energy source in our body.
And so, anything that is going to cause the build up of acetaldehyde is going to cause the toxic effects of alcohol.
Now aldehyde dehydrogenase-2, the reason I say it's a 2 is because the aldehyde dehydrogenase is a family of enzymes
and so, there's actually a 1 but we don't really care about it right now
but just a little tidbit, the 2 is a mitochondrial enzyme that's predominant job is to metabolize acetaldehyde.
The 1 is a cytosolic enzyme that has other functions.
So how does this lead us into pharmacogenomics?
Well population studies have shown that there are 2 variants of this ALDH-2. 2 variants.
And those variants are related to differences in those patient's genes.
Now fortunately, the name of the enzyme ALDH-2 is the same as the name of the gene.
And so, we have a normal version of the gene and we have an abnormal version of this gene.
And so, as scientists, we like to come up with names for things and so the way that we name the normal variant of ALDH-2 is to take a star and put a 1 next to it.
So, ALDH-21 is the normal variant and nobody likes to be number 2 so ALDH-22 is the abnormal variant
and the reason I'm giving you this information is just so we can talk about it right now.
And so these are 2 different alleles that code for 2 differnet enzymes.
Now at the genetic level, we call these SNIPS or Single Nucleotide Polymorphisms.
I'll just write here SNIPs.
At the protein level or at the enzymes, we call these enzymatic polymorphisms and we see that up here.
So, Poly meaning many and morphisms meaning forms or shapes right?
Remember, structure determines functions because we have these different genes, we have a primary structure between these 2
and thus, we have a different function.
And this is amazing because the only difference in the primary structure between these 2 is
we took a glutamate here and we made that glutamate, turned it into a lysine.
That's it. 1 amino acid difference when we look at the primary structure
but the functional difference is huge.
So going back to our Asian guy who has this flushing response, well what might've happened is
that 1 of his parents may have had this abnormal ALDH-22 or where the glutamate was replaced with a lysine
and so, when he got that 1 bad copy of it, he now becomes heterozygous and because he is heterozygous, (let me just write one bad copy)
that enzyme or the metabolism of acetaldehyde is going to be 100x slower.
This ALDH-2 is going to metabolize acetaldehyde into acetate 100x slower and as a result, acetaldehyde is going to build up.
Now, if both of his parents had a bad copy here and he got both these ALDH-22 genes, 1 from his mom and 1 from his dad,
well then he would be homozygous and in that case, that enzyme is just non-functional
and even little bits of alcohol cause the flushing and they cause nausea and they make people very averse to that alcohol use.
So, now let's take this new knowledge that you have and show you how you can apply it by looking at a paper.
So, here's a paper from the Journal of Clinical Toxicology. It's actually published this year in 2012.
And the title of this paper says, "The acute effects of ethanol which is alcohol and acetaldehyde on physiological responses after ethanol ingestion in young healthy men with different ALDH2 genotypes."
So, we talked about those 2 genotypes. One was called 1 and one was called 2.
And so, we can see how they did their methods. They took 24 men and 12 of them had this genotype.
And so, it's a 1 / 1.
So 1 / 1 means they have 2 good copies. Right, that's one for each allele
and then they had 12men with the ALDH21/2 genotype.
And so what does that mean?
That means that they have one good copy but also, one bad copy.
They are heterozygous and as a result, we already assume what's going to happen.
So, they do this double blind placebo control crossover design which is a very good study
and what they do is they give them ethanol (alcohol) and the other group has the placebo
and what they do is they measure the ethanol concentration, the blood acetaldehyde concentration
and they look at the physiologic responses of facial redness, they look at the pulse rate and the blood pressure.
So, we kind of already know what's going to happen.
In this group, with the ALDH212, the heterozygous, we know that they are going to have more facial redness than the 2 good copies
and we know that acetaldehyde is a vasodilator. It causes flushing or increased blood flow to the skin
and a compensatory response. So a vasodilator decreases blood pressure and a compensatory response is going to be an increase in the pulse rate.
And so, you can read the results on your own here
but just the conclusion, facial redness and pulse rate after ethanol ingestion were significantly higher in the ALDH212 genotype
and this was significantly associated with blood acetaldehyde concentrations.
Now, here's how this relates clinically.
If you're homozygous or you have 2 bad copies right. In that study I just showed you, with just 1 bad copy, we're getting the side effects.
Here you're getting lots of side effects.
And as a result, these people actually have a decreased chance of alcohol dependence.
And the studies have shown that the rate of alcohol abuse in people who have these double 2 bad copies of this gene is much lower
because they immediately get that flushing, it's embarrassing and they get a lot more of that side effects.
Now, for the heterozygotes, we might think that you would get the same thing,
But for a lot of these people, they can eventually develop tolerance
and if they continue to drink,
they can handle, they won't get as red in the face and what-not.
And so, these people actually have these high levels of acetaldehyde because they can drink
and what this does is it increases the risk for cancer and it increases the risk in particular from that study I showed you in that previous picture.
Where was it?
In this study. Note that - wait, they're right here.
So, the alcohol flushing response an unrecognized risk factor for esophageal cancer.
And so they have an increased risk for let's just write cancer.
So, here's a fact for you.
If you're a moderate drinker with flushing, you're at about 10x the risk of a non-flushing moderate drinker for cancer.
And so, as a clinician, you need to be conscious of the fact that there are 540 million people who are ALDH deficient
either a heterozygous or homozygous. 540 million.
And so, it's important to screen your Asian patients who get alcohol induced flushing and warn them of the increased risk of esophageal cancer.
And so, the best part here is that we don't need a genetic test to determine if our patients are at increased risk.
We can just ask our oriental patients, "Do you have a tendency to develop facial flushing immediately after drinking a glass of beer?"
Or if they've developed tolerance you could say, "Did you ever get facial flushing especially within the 1st 1 to 2 years that you started drinking?"
And if they answer yes, then you can warn them about the increased risk and hopefully get them from being a moderate drinker to a lighter drinker.
And so, the last point I want to make here is these are genetic problems that are causing a build up in acetaldehyde.
We can actually take advantage of this though pharmacologically.
We actually have a drug and I just need to mention this now called Disulfiram.
And so what Disulfiram does is it is a competitive inhibitor of ALDH2 and that causes a build up of acetaldehyde.
Now, what in the world would we use this for?
Well, it's actually used as an alcohol deterrent.
So, if a patient let's say gets put into rehab and they want to ensure that they don't drink in rehab,
they have them take Disulfiram and whenever they take a sip of alcohol, they get the nausea and the vomiting
and it just makes them very averse to alcohol use.
I actually recently had a patient who was out of rehab and was still taking the Disulfiram.
Now, patients hate it and compliance is terrible but when they're taking it, it gets them to stop drinking
but data on its long-term effectiveness is really mixed because people just don't like it.
So putting everything together, we can say that pharmacologically, we can affect the rate of drug metabolism
by giving competitive inhibitors like Disulfiram.
but also, there are genetic differences which can cause different drug responses and that is pharmacogenomics
The idea here is eventually we will develop some sort of genetic test to be able to rule out adverse drug reactions
before they happen.
And again, you don't have to memorize all of this.
The point here is for you to get the bigger picture.
So, make sure you subscribe in my channel so you can see whenever I post new pharmacology videos.
Hope to see you soon.