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Science of Skin: Retinols and Skin Health · Skin Anarchy

• 0:03
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• 0:35
  SPEAKER_01: Hey guys, welcome back to another episode of The Science of Skin.
• 0:39
  SPEAKER_01: Today's topic is retinols and their use, and we will be discussing the literature around retinol and vitamin A derivatives that has been published in the last five years, mostly in the um, you know, uh most recent two years, so 2020, 2021, and um I will be really addressing a lot of things, including the ones like the the retinol products you might get from your dermatologist's office, um, as well as something you'd pick up over the counter through a skincare line.
• 1:12
  SPEAKER_01: So I want to get started, and I'm really going to um make this episode very thorough, and it's going to be very science-heavy, so buckle in because I'm gonna start from the beginning and go all the way into the molecular um signaling and all that good stuff.
• 1:26
  SPEAKER_01: Okay, so let's start with vitamin A.
• 1:29
  SPEAKER_01: So vitamin A is really just a general term and it's um just basically referring to you know various fat-soluble substances such as retinol, retinol, palmitate, beta-carotene.
• 1:45
  SPEAKER_01: Um, it has various like metabolites, and they're all essential for things like vision, cellular differentiation, epithelial barrier function, also immune function can be regulated by these metabolites.
• 1:58
  SPEAKER_01: And um, the way that you get vitamin A into your body is through your diet, and because it's fat-soluble, um, you know, you have to ingest it.
• 2:07
  SPEAKER_01: So pre-formed vitamin A, so that's retinol and retinal ester, that is derived from animal sources such as meats, uh, fish, dairy products, all that good stuff.
• 2:18
  SPEAKER_01: Um, but then pro-vitamin A, so the precursor to actual uh fully formed vitamin A is known as beta carotenoid, and that is derived from colorful fruits and vegetables.
• 2:30
  SPEAKER_01: Um, and obviously both forms are ingested, and they have to be converted um eventually after they're absorbed through your gut, and they have to be converted to retinol and retinoic acid.
• 2:41
  SPEAKER_01: Um, and retinoic acid is really the the main guy here, okay?
• 2:46
  SPEAKER_01: So um I want to move on to what like some of the things that are around vitamin A in terms of like you know, there's a lot of stuff that's going on um with the World Health Organization where they're really focused in on um third world countries because there is a deprivation of um vitamin A, you know, in the diets of a lot of the people that are in third world countries.
• 3:13
  SPEAKER_01: Obviously, you know, because it's um you know a situation where people are malnourished, they're not getting enough nutrients, enough food to eat, they're going to be deficient in it.
• 3:23
  SPEAKER_01: And so um, you know, just to go over like what that means is that vitamin A deficiency is actually um, you know, something that can lead to a lot of problems, um, such as uh, you know, vision problems.
• 3:39
  SPEAKER_01: There's a lot of eye defects, for example, xerophthalmia is a uh condition that results um when you know you can have like night blindness, you can have total blindness, vision loss.
• 3:53
  SPEAKER_01: So vitamin A can really be used um as a supplementation to fix something like that.
• 3:58
  SPEAKER_01: Um, it can also fix you know, supplementation with it can also be offered for people with measles um or anyone with just severe malnutrition.
• 4:08
  SPEAKER_01: And this is definitely um something that's uh you know, the deficiency problem has definitely reached an epidemic level, and you know, it's it's something that is a problem in third world countries, but we don't really deal with that here, you know, in the US and and and the West.
• 4:25
  SPEAKER_01: So, but I definitely wanted to let you guys know that it's it is a problem in the world.
• 4:30
  SPEAKER_01: Um now the role of vitamin A is what I'm really interested in, and um you know, and how it's taken in.
• 4:38
  SPEAKER_01: So, you know, vitamin A, like I said, it's involved in a lot of things, right?
• 4:42
  SPEAKER_01: And it's also involved in cell morphogenesis um and differentiation as well as proliferation.
• 4:50
  SPEAKER_01: And so what that means is that it's really involved in making sure that the cells that we have are you know they're growing and they're you know, replicating and just like dividing more and more and more.
• 5:04
  SPEAKER_01: It's uh also, you know, I know in terms of marketing, it's marketed as a very strong antioxidant.
• 5:10
  SPEAKER_01: It also decreases free radical damage um on our DNA and all that good stuff.
• 5:16
  SPEAKER_01: Um, that's said in you know a lot of the marketing around uh, you know, vitamin A and all the products.
• 5:23
  SPEAKER_01: Now, you know, here's the thing.
• 5:27
  SPEAKER_01: So I want to talk about um, you know, what is so what happens to vitamin A?
• 5:33
  SPEAKER_01: So vitamin A, like if you are going to supplement vitamin A in somebody, say they're deficient, um, most supplementations are going to have to have be happening orally or intramuscularly, and then it's going to have to go through a route of absorption, which we all know fat-soluble vitamins are extremely hard to absorb.
• 5:53
  SPEAKER_01: Um, you know, they're really it there's a problem, you know, with in terms of absorption.
• 5:58
  SPEAKER_01: Then after it's absorbed, it has to be metabolized and turned into the active uh metabolites that will go and then you know do their job.
• 6:06
  SPEAKER_01: So it's quite an extensive, you know, process and it's it's it's really really complicated.
• 6:14
  SPEAKER_01: So for example, in the liver, um, you know, retinol is going to be estrified into retinal esters and then it'll be stored in the cells of the liver.
• 6:23
  SPEAKER_01: And both retinol and beta carotene are then oxidized to retinol and retinoic acid in the tissues, and then um those things are going to be essential for things like gene regulation, vision, um, whatnot.
• 6:37
  SPEAKER_01: So what really happens is that once these things are metabolized, um, the metabolites will go and they actually end up going into cells and binding onto nuclear receptors um that are found inside of the cell nuclei that we're targeting here.
• 6:54
  SPEAKER_01: But, you know, to kind of rewind it a little bit, um, we should really think about like what are the real therapeutic uses of vitamin A derivatives?
• 7:04
  SPEAKER_01: I mean, the most common one that I can tell you is for leukemia.
• 7:08
  SPEAKER_01: There's a type of leukemia called acute promyelcytic leukemia.
• 7:12
  SPEAKER_01: And what it, you know, if you think about it, what's happening here is that these uh cells in this type of leukemia, um, they're stuck in this stage of like being premature cells.
• 7:23
  SPEAKER_01: So we use, you know, a vitamin A derivative called atra, A-T-R-A, and that stands for all transretinoic acid.
• 7:32
  SPEAKER_01: And um that is used in these patients to help these cells uh differentiate further and grow further so that they can truly um just mature properly.
• 7:44
  SPEAKER_01: Um now that is the most, in my opinion, the most logical and therapeutic use of a vitamin A derivative.
• 7:52
  SPEAKER_01: Um now, obviously, we are focused on the skin, so let's talk about what's going on with the skin.
• 7:58
  SPEAKER_01: The skin, um, in in terms of skin, retinoids are defined basically as synthetic or natural derivatives of vitamin A.
• 8:07
  SPEAKER_01: Um, and they were first discovered in 1913.
• 8:10
  SPEAKER_01: Retinol and retinal esters are uh, like I said, the dietary forms um of vitamin A, and these are both not biologically active, and so they require transformation, which is what I meant when I said that we need to metabolize them.
• 8:26
  SPEAKER_01: And what happens is that when you take in the vitamin A, um you know, the the inactive form is then um, you know, exposed to these enzymes called alcohol dehydrogenases that are found in the cytosol of cells, which is like the jelly of the inside of the cell, you know, it's it's the stuff that's all around the organelles and everything, right?
• 8:50
  SPEAKER_01: So these are these enzymes are from that area, they're um going to work on the vitamin A, metabolize it, and then turn it into something called retinaldehyde.
• 9:01
  SPEAKER_01: Um, and then retinaldehyde will then be oxidized by retinaldehyde dehydrogenases, which are known as RALDH1, 2 and 3, and they will convert retinaldehyde into retinoic acid, which is referred to as RA in literature.
• 9:20
  SPEAKER_01: Okay, now physiologically, in order for um you know any retinal metabolite to interact with the nucleore receptors, it has to be transported into the nucleus.
• 9:34
  SPEAKER_01: This transport by itself is a huge feat because what needs to happen is that, for example, atra.
• 9:41
  SPEAKER_01: Um, atra needs to bind to something called CRABP.
• 9:46
  SPEAKER_01: CRABP is another protein that is required um to bring atra through all of the lipophilic barriers and into the cell and then into the nucleus, which the nucleus also has, you know, a set of membranes around it that are lipophilic.
• 10:02
  SPEAKER_01: So CRABP is really something that you know is kind of like the I guess you could say the vehicle or you know the chaperone to a to Atra.
• 10:13
  SPEAKER_01: And so what's happening is that um, you know, it they're both combining and then being able to enter the nucleus.
• 10:20
  SPEAKER_01: Now, CRABP2 is the one that is the most prominent in the skin, and it has been proposed to be a marker for uh retinic acid activity in the human skin, and expression of CRABP2 can be induced by atra and it can also be reduced in aging human and mouse skin.
• 10:43
  SPEAKER_01: So research has been showing, you know, for a while that there is a big role of CRABP2 in skin aging.
• 10:50
  SPEAKER_01: They've studied like knockout mice that don't have the CRABP2 gene in them, and so you know, when they studied these mice, um they saw that there was a reduction of keratinocyte layers, there's a reduction of the degree of proliferation, differentiation of cells, um, there's a decrease in skin thickness.
• 11:09
  SPEAKER_01: Um, all of these things were noticed in these mice that lacked this gene.
• 11:13
  SPEAKER_01: Now, obviously that makes sense because we know that you know retinoic acid and retinol or vitamin A, it's involved in all those things we just discussed, right?
• 11:22
  SPEAKER_01: So cell proliferation, differentiation, all that stuff.
• 11:25
  SPEAKER_01: Um and you know, obviously in these mice they would see things like uh there was the loosening of collagen bundles, and uh there's a lot of things that contribute to like just aging skin in general.
• 11:39
  SPEAKER_01: Now that's that's interesting because that's looking at a model that's very, very um isolated.
• 11:45
  SPEAKER_01: It's an isolated example because in this case they're just completely missing that that gene that goes for this very essential protein that's required for um you know vitamin E uh metabolite to actually do what it's supposed to be doing.
• 11:59
  SPEAKER_01: Um so we can't really look at that and say, oh wow, yeah, there's a huge effect of you know, we need it, we absolutely need it.
• 12:07
  SPEAKER_01: Um, so you know, this really moves makes me move on to the next uh segment of this, which is gonna be a lot more um, you know, signaling uh focused.
• 12:17
  SPEAKER_01: So I want to talk to you guys about like what so what happens, right?
• 12:20
  SPEAKER_01: So what happens with these metabolites?
• 12:22
  SPEAKER_01: Where do they go?
• 12:22
  SPEAKER_01: What do they bind?
• 12:23
  SPEAKER_01: Um, you know, what's really happening on that you know cellular level.
• 12:28
  SPEAKER_01: So what's what's going on is that this there are uh retinoic acid receptors, RARs, and there's three types there's alpha, beta, and gamma, and then there's also another uh retinoic acid receptor that's known as RXR, which is actually found in a lot of different places in the body.
• 12:48
  SPEAKER_01: So RAR, uh RAR alpha, gamma, and RXR are all three of those are really highly expressed in fibroblasts and keratinocytes.
• 12:58
  SPEAKER_01: And RAR alpha is the most abundant of the three in fibroblasts.
• 13:04
  SPEAKER_01: Now there is another one called, like I said, RAR beta, and that really doesn't have any expression at all.
• 13:09
  SPEAKER_01: It doesn't really have a role in the skin, but if you expose um, you know, the skin to you know retinic acid, it'll rapidly induce the expression of RAR beta.
• 13:22
  SPEAKER_01: So really it's like, you know, if there's no RAR beta, you know, it's okay because like the skin once it's induced or when it's uh exposed to it, it'll start expressing that receptor.
• 13:36
  SPEAKER_01: But on basal levels, on normal physiological levels, there's no real role of RAR beta, that specific receptor.
• 13:43
  SPEAKER_01: Now in the human epidermis, there is an abundance um of a specific heterodimer known as RAR alpha uh combined with RXR alpha.
• 13:55
  SPEAKER_01: This is a complex, so you can think of it as like a super receptor because what's happening here is that you know RAR is um, you know, like basically the there's a conformational change that happens to RAR alpha, that that initial receptor, and that conformational change allows it to then be coupled to RXR, which is gonna then form this uh you know double this double receptor complex, right?
• 14:23
  SPEAKER_01: And now this RAR alpha slash RXR alpha complex, this is going to be mostly found in the basal layers of your skin.
• 14:32
  SPEAKER_01: Now, basal, you know, you guys can imagine are is are the deeper layers.
• 14:36
  SPEAKER_01: Now another uh complex is known as RAR gamma combined with RXR alpha.
• 14:42
  SPEAKER_01: So RXR alpha again can combine with both the alpha and the gamma um, you know, subtypes of RAR, which is retinic acid receptor in the skin.
• 14:54
  SPEAKER_01: Okay, so the RAR gamma and RXR alpha uh super receptor complex, this one specifically is going to be more common in the supra basal layer of the skin.
• 15:05
  SPEAKER_01: So this, you know, those are the receptors that are there.
• 15:09
  SPEAKER_01: Now these are both obviously they're they're found in in uh the deeper layers, right?
• 15:14
  SPEAKER_01: So we have to also keep that in mind.
• 15:16
  SPEAKER_01: Now what happens?
• 15:17
  SPEAKER_01: So once atra goes and um binds to its ligand-binding domain, the RARs, um, like I said, they go through this conformational change and then they allow for the heterodiamerization or aka combining with RXR.
• 15:36
  SPEAKER_01: So it's really this this binding of ATRA initially onto the retinic acid receptors, so either the RAR alpha or the RAR gamma, and then those will change and they'll allow for this, you know, um binding or this uh what do you call it?
• 15:53
  SPEAKER_01: Uh combining with RXR alpha.
• 15:56
  SPEAKER_01: Okay, so that's how it works.
• 15:58
  SPEAKER_01: But RAR is not the only thing can that can partner up with RXR.
• 16:05
  SPEAKER_01: RXR, like I told you guys, is found in multiple tissues in our body.
• 16:08
  SPEAKER_01: RXR is found in, for example, thyroid hormone um or thyroid uh is found in you know all over the body.
• 16:15
  SPEAKER_01: So it can couple with receptors like the thyroid hormone receptor or the estrogen receptor or um androstane receptors or vitamin D receptors, other nucleore receptors, and it can partner up with all of those different types of receptors and and form the same super uh you know receptor complex in various tissues.
• 16:36
  SPEAKER_01: So that's something to really uh keep a focus on, okay?
• 16:40
  SPEAKER_01: So the broad range of retinolic acid's effects through um what is known as nine cis retinic acid, which is a metabolite of retinic acid, is not induced solely by the RAR slash RXR uh, you know, combination or you know, the the mechanism that happens once those two receptors combine, but it's also um by the physiological effects of activation of the RXR um in other tissues when it you know combines with other receptors like the thyroid hormone receptor and stuff.
• 17:14
  SPEAKER_01: So it can really act on anything that RXR is combining with and forming this uh complex with.
• 17:22
  SPEAKER_01: Okay.
• 17:23
  SPEAKER_01: Now um I mentioned nine cys RA, right?
• 17:26
  SPEAKER_01: So Atra has uh like isomers, and so one of them is nine cys RA, and this nine cys, what that means is just the organic chemistry uh designation of saying on carbon-9, you know, there's like you know, there's this group attached on carbon nine in cis means in the same direction, trans means in opposite direction.
• 17:50
  SPEAKER_01: So it's that's what those designations mean.
• 17:52
  SPEAKER_01: So there's these two um prominent isomers that are really discussed when it comes to the skin and uh retinoic acid, and they are the nine cis and the thirteen cis RA, and they are naturally occurring ligands, or you could call them keys for the retinoic acid receptors.
• 18:10
  SPEAKER_01: They bind all three of the RARs, so um they bind all three, so alpha, beta, and gamma, but they have different affinities for each of them.
• 18:19
  SPEAKER_01: So nine cis, for example, has a really high affinity for um you know uh RAR, alpha, beta, and gamma, as well as RXR, and uh but the highest affinity is for the alpha uh subtype.
• 18:35
  SPEAKER_01: Okay um now in terms of you know in terms of like what happens with you know once it binds and what's going on afterwards, there's a huge cascade of events that happen after these receptors are bound by retinic acid and you know the signaling that's happening downstream.
• 18:59
  SPEAKER_01: So what happens is that you know once they're bound, they're going to activate a lot of different signaling cascades downstream that are going to be like, you know, for example, um, what do you call it?
• 19:13
  SPEAKER_01: Uh uh kinases.
• 19:17
  SPEAKER_01: So kinase cellular kineses get activated, and uh what that hap what kinases do is they phosphorylate things.
• 19:24
  SPEAKER_01: So they're gonna phosphorylate other um, you know, uh d downstream proteins that are going to then be activated and work on other, you know, signaling and then cause other effects, and then overall you're getting this, you know, when we say things like uh, you know, atra or retinoic acid is involved in cell proliferation differentiation, well, it's because all of these signaling cascades are happening and it's eventually leading to this effect that we're talking about, okay?
• 19:53
  SPEAKER_01: And the exact mechanisms I just want to highlight that are underlying these non-genomic effects of atra are really not fully understood.
• 20:03
  SPEAKER_01: And um, they can have very important consequences, and they have to be taken into real consideration when we're uh talking about retinoids and what they do to different cell types and different organs.
• 20:16
  SPEAKER_01: So this is something that I really want to highlight because I think uh a lot of people don't want to talk about that, and that's something that's very important to understand, especially with a lot of the articles that come out that are saying, you know, um retinols have been prescribed before, and they've led to, like, for example, infertility in young boys, they've led to damage of you know reproductive organs for both boys and girls.
• 20:38
  SPEAKER_01: This is all these are all conversations that revolve around this molecular action of retinoic acid and how it binds, and how it is not a very specific um, you know, binding uh you know uh process that's occurring here.
• 20:53
  SPEAKER_01: There's there's a lot of ifs, ands or buts, you know, there's a lot of gray area around this.
• 20:59
  SPEAKER_01: So moving on, you know, I want to talk about how you know what what goes on.
• 21:05
  SPEAKER_01: So like I said, you know, Atra in cells, in skin cells, it depends.
• 21:11
  SPEAKER_01: It depends on what's going on in terms of like the complexity of the interaction on both the genomic and non-genomic pathways, and it that really is just not fully understood.
• 21:24
  SPEAKER_01: And um, you know, this leads me to my next point of uh, you know, what really happens to these metabolites in our body.
• 21:31
  SPEAKER_01: Now, our body is normal naturally designed to not like retinoic acid metabolites.
• 21:37
  SPEAKER_01: So, what I mean by that is that our body, all of us have this group of enzymes called cytochrome P450 enzymes.
• 21:45
  SPEAKER_01: These are the um main enzymes that are uh synthesized in our liver, and they are involved in basically degrading and breaking down any drug, any drug metabolite that we ingest, anything in our body.
• 21:59
  SPEAKER_01: And this is a This is our biggest and most prominent way of degrading and getting rid of these metabolites of drugs.
• 22:08
  SPEAKER_01: Okay, so cytochrome pre-450 enzymes are really important to talk about here because there is a huge role that they play um in terms of the response they have towards retinoic acid.
• 22:21
  SPEAKER_01: Now um cytochrome pre-450s can cause a deficiency of retinoic acid because they really don't like it.
• 22:29
  SPEAKER_01: They want to break it down.
• 22:31
  SPEAKER_01: So this leads to a whole different issue, right?
• 22:34
  SPEAKER_01: Because their natural response is no, we don't want this.
• 22:38
  SPEAKER_01: We want to break it down, get rid of it.
• 22:40
  SPEAKER_01: And so what happens in a lot of people who have some serious skin pathologies like hypercurotinization or um, you know, they have psoriasis or something really serious is that um you know cytochrome P450s are really uh playing a role here because they're breaking down retinoic acid, which we're trying to give these people in order to help them with these uh pathologies.
• 23:02
  SPEAKER_01: So to overcome all of this, there have been some strategies that have been created and um you know uh that are associated with, like, for example, like the exogenous use of atra.
• 23:14
  SPEAKER_01: Um, and they're based basically on the modulation of increasing the levels of atra that are available inside of the cell, right?
• 23:23
  SPEAKER_01: And so uh and but how we do this, we do this by inhibiting the atra for hydroxylase enzymes.
• 23:31
  SPEAKER_01: Um, these these are the enzymes that are uh really responsible in terms of breaking down atra.
• 23:37
  SPEAKER_01: Um, the inhibitors that uh that inhibit these enzymes are referred to as RAMBAS, so the R A M B A.
• 23:45
  SPEAKER_01: So these are something you guys can actually ask your dermatologists.
• 23:48
  SPEAKER_01: You know, when next time you go to a dermatologist, I really urge you to talk to them about a little bit about this, and they can really, if you know, they're well versed in the literature around retinols, they should know about this stuff and they should be able to tell you more about this.
• 24:03
  SPEAKER_01: But you know, um Rambas are really very important in the in terms of using atra and using atra-mediated therapies in terms of uh these serious uh skin pathologies like like I mentioned above.
• 24:16
  SPEAKER_01: Um, you know, so look, you know, let's talk about Rambas.
• 24:20
  SPEAKER_01: So Rambas, like how do they work, right?
• 24:22
  SPEAKER_01: They broke they block this enzyme, like I said, the for uh the for hydroxylation um of the all trans retinoic acid, so atra.
• 24:32
  SPEAKER_01: And this um this all depends on cytochrome p450 enzymes.
• 24:39
  SPEAKER_01: So what is really happening is that cytochrome P450 is at the rule like these enzymes are at the center of the degradation of atra.
• 24:50
  SPEAKER_01: So when you inhibit them, they're gonna there's obviously, you know, if you inhibit these enzymes, there's going to be an increase in the overall concentration of atra inside of the cells.
• 25:00
  SPEAKER_01: So that, you know, we're we're suggesting that by increasing that concentration, we're actually having more therapeutic effects that are going to do things like block aging, and they um, you know, can really work on the pathologies that we're we're really kind of getting at here.
• 25:18
  SPEAKER_01: But you know, the regulation of atra inside of a cell and this the its isomers, it's really something that we have not studied.
• 25:29
  SPEAKER_01: It's something that, you know, we've looked at in terms of like cancer therapy, but we really haven't studied that extensively in dermatological diseases.
• 25:38
  SPEAKER_01: You know, there's for example, Rambas are, you know, um, a lot of them, the first one ever to really come onto the scene was this drug called ketoconazole, and ketoconazole is a antifungal, and it was, you know, um something that was used to you know treat things that were just like fungal infections, right?
• 26:00
  SPEAKER_01: Of the skin.
• 26:01
  SPEAKER_01: And um this was like one of the first times we saw this uh idea of using a Ramba associated drug, and you know, from there we you know, we've kind of had some other iterations that are um you know a little bit more specific, you could say, but there's still a lot of clinical trials, you know, even the literature says, you know, um there's a lack of clinical trials, there's a lack of true studies that um are showing the effects and the benefits of the long-term use of these drugs, whether it's for a serious skin pathology or for something um not so serious, like a lot of us, like wrinkles, you know, it's it's one thing to, you know, and and this is something I really want to address is that it's one thing to use um you know these these drugs in in the care of patients who have serious skin conditions, like psoriasis and skin cancers and all of these things, but it's a whole different thing when you're looking at n I guess what you would consider normal physiological skin.
• 27:07
  SPEAKER_01: There's a whole different um context that needs to be really addressed here.
• 27:12
  SPEAKER_01: So, you know, I just wanna I I really want to stress that and I want everybody to really keep that in mind um when they think about retinols and and why we're using them and who needs to be using them more important, you know, more importantly.
• 27:26
  SPEAKER_01: So, okay, so with all of that in mind, you know, um there you I I just wanna, you know, I just want to make sure that we we understand that.
• 27:37
  SPEAKER_01: Now, in terms of the cytochrome P450 enzymes that I mentioned, I do want to also mention that the main one that is uh really involved in the metabolism of ATRA is cytochrome P450-26A1.
• 27:51
  SPEAKER_01: This is a major enzyme.
• 27:52
  SPEAKER_01: It's actually not specific to retinoic acid, it's it's involved in the metabolism of a lot of different drug metabolites.
• 27:59
  SPEAKER_01: Um, we learned this pretty heavily in medical curriculum.
• 28:02
  SPEAKER_01: So if any of you are listening in and you're dermatologists or your doctors or have medical background, I'm sure you guys know exactly what I mean.
• 28:09
  SPEAKER_01: I mean, this one specifically 2681 is something um it's it's uh you know uh cytochrome P450 that we really do learn about and it's used you know its use is is very vast, you know.
• 28:25
  SPEAKER_01: So uh that I just wanted to mention that's the exact one that is involved in the degradation, the breakdown of ATRA.
• 28:31
  SPEAKER_01: So if you're going to inhibit that cytochrome P450, keep in mind that you're also inhibiting its ability to degrade other drug metabolites that are coming from other things that we ingest that has nothing to do with the skin.
• 28:45
  SPEAKER_01: It might be drugs that you're taking over the counter for um muscle aches or you know, whatever.
• 28:51
  SPEAKER_01: There's a lot of stuff here that you know there's a lot of overlapping, you know, uh relevance here in terms of inhibiting that specific cytochrome P450 enzyme.
• 29:03
  SPEAKER_01: So that's very, very important to keep in mind.
• 29:07
  SPEAKER_01: Now, you know, the next thing I want to really focus on focus on is that, you know, in terms of like the concentrations, you know, that have been used and studied in uh, you know, for uh being able to inhibit uh the catabolism of atra, right?
• 29:27
  SPEAKER_01: Those have only shown like they've used pretty high concentrations, and those even at those concentrations, there's only been a very small inhibitory effect seen.
• 29:37
  SPEAKER_01: Um, you know, so it's it's really not something that has been properly studied.
• 29:42
  SPEAKER_01: It's something that is definitely still in the making.
• 29:44
  SPEAKER_01: You know, we really the literature does not support this vast use of retinols.
• 29:50
  SPEAKER_01: It it just doesn't.
• 29:51
  SPEAKER_01: That's and that's on me being completely transparent, completely honest, there's just not enough evidence there for the use of retinol for normal, um, you know, physiological, physiologically stable skin types.
• 30:05
  SPEAKER_01: So that's you know, I'm not gonna deviate from that statement.
• 30:08
  SPEAKER_01: I mean, if someone wants to uh rebuttal that statement and and cut, you know, kind of correct me, please, I would I really urge you to show me the literature because I haven't found it.
• 30:18
  SPEAKER_01: Um, you know, it's something that I think a lot of people really need to study and they need to learn about because um, yeah, okay, there's some effects, you know, that or some benefits that we can really focus on, like, you know, in terms of photo aging or age-related hyperpigmentation or actinic uh keratosis um that can respond really well to Rambas.
• 30:42
  SPEAKER_01: But overall, the key here is that most of the human studies that have been done have focused on photo-damaged or photo-aged skin.
• 30:52
  SPEAKER_01: And there has been very little information published, if any, um, on the effects of tretinoin on chronol, you know, chronologically or intrinsically aged human skin.
• 31:05
  SPEAKER_01: That's called normal aging of skin.
• 31:07
  SPEAKER_01: So unless your skin is aging because it's being exposed to excessive levels of sunlight or you know, severely damaged, um, you know, there's there's no evidence that these drugs work on normal aging, nor normally aged skin.
• 31:23
  SPEAKER_01: And that's something I really hope you guys can take away from this uh, you know, episode is that retinol have their purpose.
• 31:31
  SPEAKER_01: Yes, they're they're approved and they're used clinically, but they're supposed to be used for patients who have serious skin pathologies.
• 31:39
  SPEAKER_01: Their use is designed for that.
• 31:41
  SPEAKER_01: There's not any evidence that they are um beneficial for normal aged skin.
• 31:47
  SPEAKER_01: There's no evidence that suggests that their use can really benefit people, um, you know, of all demographics, all you know, backgrounds, everything.
• 31:58
  SPEAKER_01: Um and so, yeah, it just it it doesn't make any sense.
• 32:08
  SPEAKER_01: Um, so I do want to say this though, before I end this episode, that I'm not saying that we don't need vitamin A.
• 32:13
  SPEAKER_01: So um if any of you have been listening and you know, if your critique is going to be towards that, I'm definitely not saying that obviously we need vitamin A.
• 32:21
  SPEAKER_01: It's a very crucial vitamin for a lot of things, like I mentioned, you know, in a lot of detail in this entire episode, vision, you know, normal proliferation of cells and differentiation of cells.
• 32:33
  SPEAKER_01: But what I'm saying is that the topical application of uh, you know, vitamin A derivatives is not something that we need for physiologically, you know, normal aging.
• 32:45
  SPEAKER_01: Now, a lot of people might say, well, Ecta, you know, we have photoaging happening every single day.
• 32:50
  SPEAKER_01: Well, not necessarily the case.
• 32:52
  SPEAKER_01: Okay, you might be photo-aging a little bit, but if you're uh already practicing good skin health uh practices, such as wearing sunscreen on the daily, protecting your uh skin from excessive, you know, sun damage or sun exposure, uh staying inside, which a lot of us do, especially with how COVID has been and the pandemic, you're probably not dealing with um excessive photo damage to your skin.
• 33:16
  SPEAKER_01: So that's my point here is that I definitely believe that retinol, um, you know, retinol has its purpose in clinical health and the use of it, you know, from the perspective of clinicians.
• 33:29
  SPEAKER_01: But in terms of the molecular pathways and in terms of the actual studies that are out there, I mean, you know, it's kind of like give or take.
• 33:39
  SPEAKER_01: And it's also more of an ide uh, you know, the concept of do we need it or not?
• 33:44
  SPEAKER_01: And so it should be, I think, more than anything.
• 33:47
  SPEAKER_01: I'm not saying get rid of it, I'm saying be more selective in who you prescribe it to.
• 33:52
  SPEAKER_01: I know that there are some phenomenal, phenomenal dermatologists out there, but obviously there are also some um physicians and some, you know, practitioners that are just a little bit more loose with prescribing certain things, you know.
• 34:05
  SPEAKER_01: I think that the analogy of antibiotics is kind of um a little, you know, it it fits here because you know, you you can prescribe antibiotics, right, uh, pretty easily uh as a doctor, but should you every time?
• 34:19
  SPEAKER_01: Probably not, right?
• 34:20
  SPEAKER_01: Because of resistance issues and all sort all sorts of stuff, right?
• 34:24
  SPEAKER_01: So same with everything that we prescribe.
• 34:27
  SPEAKER_01: We have to be very um, you know, not just cautious, but very thorough in our approach and understand why we're prescribing what we're prescribing and and make sure that it the patient really needs it.
• 34:39
  SPEAKER_01: And also, um, for patients out there, don't go to your doctor and say, I want a retinol.
• 34:44
  SPEAKER_01: You might not need it, you know.
• 34:46
  SPEAKER_01: I mean, there are so many options, especially today in skin health.
• 34:50
  SPEAKER_01: So, anyways, um, I don't want to rant, but I really just wanted to educate everybody based on the literature that I found, um, the way that I read it and took out all of the key points.
• 35:00
  SPEAKER_01: So, if you have any questions, if you need me to clarify anything, please reach out.
• 35:03
  SPEAKER_01: I'm very much open to anyone's questions, critiques, um, you know, feedback or additions to this episode.
• 35:09
  SPEAKER_01: Definitely keep the conversation going in the comments.
• 35:12
  SPEAKER_01: Um, I would love to entertain any and all um, you know, commentary.
• 35:17
  SPEAKER_01: All right, guys, thanks for listening to another episode of Science of Skin.
• 35:21
  SPEAKER_01: I know that you're still waiting for me to bring on people um and have this be a more uh, you know, like an interview kind of thing, but I'm kind of having fun, you know, just kind of discussing topics that are very important in skin health.
• 35:32
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• 35:43
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• 35:49
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• 35:56
  SPEAKER_01: Thanks, guys.
• 35:57
  SPEAKER_01: Have a wonderful, wonderful weekend.
• 36:03
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