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0:06
all right so it's going to get start on xenobiotic metabolism what is xenobiotics we should really get an understanding of that first before we start talking about all this other stuff so xenobiotics they are basically any particular substance that is not naturally present in the body or it's not produced by the body or it's in higher concentrations than usual within the human body okay we're primarily going to refer to these as drugs this is the detoxification function of liver so
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whenever you hear people talking about all man delivers a detoxification center it is and some of the things that it can detoxify are metabolized is tons and tons of different types of drugs that we take on a daily basis or certain types of toxins that might even be present in the body as well all right so let's go ahead and get started on this so when we talk about xenobiotic metabolism we have to remember that there's gonna be two phases of xenobiotic metabolism so we're
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gonna take a little scenario here let's say that we take in some type of drug doesn't matter what it is we take in that drug we ingest it let's say we take it orally we get it absorbed across our digestive system right into the Apothic portal system and then it gets taken to the liver when it gets taken to the liver let's follow and see what happens so let's go ahead and represent this like here let's do like this like a little pill here's gonna be like our little
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pill right there right so here's the pill this is the drug now we are going to start metabolizing right here okay now usually the drugs that we have inside of our body are usually hydrophobic okay in other words they don't like to you know mix with water so usually because of that they have tons of hydrogen's so they're saturated with hydrogen's which again is not very good for interacting with water okay so one of the things that we want to do right away when we get this drug into the
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liver is we want to send it to specific organelles located within the apat asides so here let's draw let's use this here is going to be a nice little endoplasmic reticulum so in your liver you have these things called smooth endoplasmic reticulum alright and this guy is super important there's tons and tons of enzymes in here like look let's actually have like one enzyme right here look there's one enzyme and he's gonna be present in here and this is a gonna be a group of enzymes that are super
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super crucial in the metabolism of a bunch of different types of drugs what is the name of this enzyme group okay this is super important you have to remember this one this is your cytochrome p450 complex what in the heck does that mean what did the heck is cytochrome p450 cytochrome p450 it's obviously a it's gonna be a certain type of protein that contains a heme within it right kind of just like hemoglobin now this protein complex is super super critical for us detoxifying
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these drugs now what the heck does this 450 come from what does that mean so cytochrome is the family it's the super family of enzymes 450 comes from if you take a cytochrome like a heme molecule and you bind it on to carbon monoxide the maximum wavelength that that pigment can absorb is around 450 nanometers so that's where that 450 comes from so again cytochrome p450 is a group of enzymes it's a super family of enzymes that are super super important in the
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metabolism of these xenobiotic chemicals okay so let's go ahead and see what happens first now the cytochrome p450 what are they gonna do to this drug let's say we bring this drug lee shuttle it in here into the smooth endoplasmic reticulum so what is this right here this is our smooth ER or endoplasmic reticulum there's a group of these enzymes cytochrome p450 what are they going to do to this drug these are primarily the cytochrome p450 complex is primarily what's called oxidases
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in other words they love to introduce oxygen into this drug compound so what are they going to try to do their function is they're going to try to introduce or insert a oxygen atom into the compound that is their significance okay now these are going to be the primary ones okay so what are they going to do so let's say we take this drug here we have it interact with the cytochrome p450 complex after they interact with it what they will do is they'll take an ad on they'll insert and
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oxygen into this usually by what's called hydroxylation reactions it could be oxidation it could be reduction reactions it could be hydrolysis reactions but we're gonna say that what it's going to do is it's going to insert the oxygen onto this drug so now what we're gonna see is something like this an OHA this is super polar okay this is going to be super super import because the whole purpose of the xenobiotic metabolism is to take a drug that's not really polar pretty hydrophobic and turn
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it into something that's more polar things that can either dissolve or be soluble within our urine soluble within our fecal matter or maybe even soluble within the blood plasm so we can go and send it to different organs that we need that drug to be useful for okay so that's important so first thing we're gonna do is perform this oxidation reaction so again what kind of reactions would it do it could do a couple it can do oxidation reactions it can do what's called reduction reactions it can do
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what's called hydrolysis reactions super super important that we understand that for the cytochrome p450 complex okay now for this cytochrome p450 complex there's a bunch of different enzymes that compose it what are some of the enzymes that make up the cytochrome p450 I want you not to remember all of them I just want you to remember a couple of them that are super super important what are some of these one of the big ones if you don't remember any of them please at
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least remember this one this one is called C YP 3a for now here's what I want you guys understand cyp is the super family 3 represents the family a that letter right there it's representing the subfamily and then 4 is representing the gene that's producing the proteins responsible for the metabolism of these drugs this one is super important ok so again what does this stand for here let's do it in different colors so we can make sense of it so cyp let's do here purple is going to be 3 we'll do
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red as a and then we'll do 4 as this maroon color actually let's make it completely different let's do pink ok so again the cyp this stands for super family so it stands for super family it's a super family of enzymes the 3 that purple color that's representing the family ok the red is representing the subfamily ok so this is the subfamily and then the last one which is the pink and that is specifically representing the gene the gene won't lead to the transcription of a
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particular arm an mRNA that will be translated to a particular protein that will function in this metabolic process so again this is going to be the gene that'll lead to the particular isozyme alright so that's important now why is this one specifically important because it is the one that controls the metabolism of 50% of the available drugs out there on the market you can see why now this one is the most important to remember so he controls almost 50 percent of all the available drugs out
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there that's how many drugs he can metabolize pretty pretty important one more that's really important and it's important because of clinical reasons another one it's called cyp i'll stay consistent with the caller's 2d6 2 again representing the family d here in red representing the Saab family and in the pink which represent the production of a particular protein there that is going to be a very very important one clinically okay there the reason why this one's important is there certain
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polymorphisms okay so different types of polymorphisms can lead to certain people having different variants in that gene so what do I mean some people in this particular gene might be slow metabolizers okay so some might be very slow metabolizers in other words they don't produce a lot of this particular enzyme so they can't metabolize a particular drug okay other ones which is super super important to remember can be what's called ultra-rapid metabolizers okay what does this mean
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so what this means is let's pretend here okay we'll actually not pretend but let's be specific this enzyme is very very critical to metabolizing a particular drug do you know what that drug is called it's called Cody so here's the drug right there and what it's responsible for doing here is this responsible for taking a drug called Cody and when it metabolizes codeine it turns Cody into another molecule that we all have pretty familiar with and this is going to be
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called morphine it's used in a lot of you know trying to be able to treat pain let's pretend that someone is a slow metabolizer of this particular substance what's gonna happen are they gonna be able to have that analgesic effect when they're in pain no what about someone that's an ultra-rapid metabolizer and you give them codeine what can happen they'll start producing morphine at super high concentrations which can cause very very very serious side effects especially if given to children
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this can cause obviously death it can be super fatal so it's super super important to understand just these two specific cytochrome p450 enzymes okay this one please remember this one it counts for 50% of the available drugs that can be metabolized and this one is specifically important because of polymorphisms that are kind of common and that particular allele some people can be slow and some people can be ultra rapid which can be very dangerous okay all right so now we have
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a pretty good understanding of what's happening here with this cytochrome p450 complex we're taking the drug we're inserting an oxygen into it whether it be through oxidation reject reduction or hydrolysis reactions but we're primarily trying to hydroxylate so what's the significance here and this step here this first step is we're trying to hydroxylate the drug produce an OE after that we can take this drug that we've made slightly polar right slightly polar not polar enough but slightly
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polar and we can take it to specific enzymes there's tons and tons and tons of these enzymes so for example let's say that I had a group of these enzymes let's say here I have one guy here okay and this enzyme he's the one of the most common okay that is gonna react with this drug here look at this guy super taube this enzyme is called we're gonna label it ug t udp-glucose l'll transferase super important enzyme if you don't remember any of these other enzymes that
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I'm gonna mention please remember this one he is the most common enzyme that's gonna be involved in this and next step so what can happen is is let's say that we take this drug right here that we've hydroxylated right we've made it slightly more polar we take and reacted with this enzyme here what this enzyme does is is you have to think about the name it's called udp-glucose I'll transferase it's basically a glue qurani molecule glue car on aids are super super polar they
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have a bunch of they have carboxylic acids and hydroxyl groups all over the place so because of that now what I'm gonna do is is I'm gonna take this drug here and what I'm gonna do is I'm going to add on I'm going to get rid of that H and I'm going to add on the glue Quran eat so now what I'm gonna do is I'm not going to show the structure not necessary here I'm just gonna put here a G for the glue grenade okay and this blue car on it what I want you to remember is super super polar so now
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this drug that we first had that was super nonpolar we made it extremely polar okay so now that is super important and we made a polar so again what stuff what do we start off with with this drug with just the one hydrogen super nonpolar super hydrophobic then what do we do we took it through this cytochrome p450 system hydroxylated it and we made it slightly polar so we made it slightly polar and then we kick up the juice and we're reacting with these specific
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enzymes like ug t which can add a glue Gore on a group onto it and make it very polar what are some of the other enzymes okay some other ones that we should know about let's do orange here let's say here's another dude they're all kind of pretty much the same let's saying they're all Toby this one's another important one super important one it's called glutathione s transferase okay glutathione s transferase so now what do you think it's doing it's transferring a
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glutathione molecule onto this drug here so now we can take this guy send it through this reaction and what am i gonna have here now I'm gonna have my drug here with the oxygen and it's gonna be attached now to a glutathione molecule let's represent this with just a G again but different color and that glutathione molecule again is super charged and polar we now just made this molecule a lot more polar and again we'll also talk about another significant thing about glutathione
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which that is very very important antioxidant molecule we'll talk about that when we talk about alcohol metabolism okay what are some other enzymes let's just keep going through here let's just keep banging these suckers away another really important enzyme is actually going to be called yes el-tee okay and this stands for sulfa transferase enzymes sulfa transferase enzyme that are also really important because they react with particular drugs and guess what they're
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gonna do they're gonna add a sulfate group on to it so now we can have here what we'll have our drug and what do we just add on to it we added on a sulfate group and sulfates have a bunch of negative charges on them too a bunch of different oxygens on them and again that's gonna make this molecule super charged and super polar there is other ones I'm not going to spend a significant amount of time talking about every single one of them will mention one last one that is crucial here and
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that'll finish up here let's do this next one let's do this guy in black and here's our last one here and here's his face he's excited to help in this metabolism here he's a chunky guy too and this is going to be in let's put in a tea in a tea okay net and this guy is called in acetyl transferase what do you think he does he adds in a siedel group he adds an acetyl group onto whatever the drug molecule is again trying to make the molecule more polar okay so let's represent that last one
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there with a acetyl group now what did I say was the most significant one that I want you guys to remember let's mark it let's not forget him it's this one super super important we'll talk about it in the biliary system any type of deficiency in this enzyme can produce some very severe issues one is called Craig ler and a jar syndrome very very fatal if not treated another thing that can happen is what's called gray baby syndrome if a child is actually born with a low
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glucuronidation glucuronidation at capacity and you give them chloramphenicol it can cause this baby to have a great action appearance and it can be very very dangerous and can cause complete circulatory collapse if not treated quickly so again super-important so now what did the liver jizz do we have names for this phase in this phase this phase here where we utilize the cytochrome p450 enzymes which were located within the smooth endoplasmic reticulum you know what else we call
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them we call them microsomal that's actually mind write this down this they're called our micro so there's a bunch of cytochrome p450 enzymes you probably heard of some of them cytochrome electron transport chain within the mitochondria it's the same type of enzyme same basic structure so it's super important that you understand that this is located within the smooth endoplasmic reticulum whereas when other people think about cytochrome the thing about electron transport chain okay so it's super
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important to remember that this phase this phase right here where we took the drug and put a hydroxyl group on to it where we hydroxylated it this is called phase one okay and the purpose of phase one is to utilize the cytochrome p450 system to introduce an oxygen into the drug making it more polar unfortunately it's not good enough we have to do something else we have to take that slightly polar drug and then send it through some specific conjugation reactions so what is these reactions
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here called let's highlight right under all of them these are called conjugation conjugation reactions and this conjugation reaction which we utilizes an acetyl transferases UDP glucose i'll transferases glutathione ash transfer ASIS sulfa transferases so many other ones these are responsible for the conjugation reactions and this is called phase 2 ok and again we'll talk about some of the diseases were associated with this particular enzyme whenever we talk about the biliary system but again
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remember that we'll also talk about another function here when we get into the biliary system because now these drugs now that we've actually completely made them polar they have a couple destinations again we'll get into more details I'm just gonna take here and I'm gonna put a generic thing on I'm just gonna put an R group on here which represents the conjugated substance which could be an acetyl a glue Quran 8 it could be glutathione or it could be sulfate what we'll do with this drug now
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that's super polar is it has to be eliminated okay or excreted so now it has to diverge and go to three different ways okay we could take it and actually put it into the urine to be excreted out we can actually send it and put it into the blood plasma to have it go and function wherever it needs to function or weakest excreted out in the bile okay and that's important and we'll talk about this whenever we take this drug now what can we do and we utilize specific transporters for all of these
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and we'll talk about them for example when we talk about bio super important to remember what's called in dr1 it's a specific transport that excretes this actual drug out into the bile whereas these ones right here you can use things like organic anion transport proteins and again we'll talk about these whenever we talk about the biliary system but this part where we excrete it so this part here where it can be let's say secreted okay this is Phase three okay and this is basically the secretion
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/ excretion okay all whatever that drug might be okay super important that we have a good understanding of that okay so the liver would be thankful for this guy because he does a lot of cool things for us okay next thing I want to talk about something else that is super super important we should understand what the liver we face it it's a super epidemic in this life we hear about it all the time and that's alcoholism okay the liver is super super crucial to that alcohol metabolism but it doesn't
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utilize this normal cytochrome p450 system kind of let me explain what I mean here let me take here alcohol so let's say here we have our alcohol okay and the alcohol that we usually are ingesting okay is in the form of what's called ethanol ethanol which we usually I can represent here as EtOH okay that alcohol when we ingest it you know where it's actually absorbed it's absorbed across our stomach and taken up via the PAP addict portal system to the liver now here's the thing
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this alcohol once it's in the liver it has three pathways that it can go through okay one pathway that it can go through utilizes let's actually draw here like a little green tube look at this guy okay he's gonna be going through this pathway here okay now this right here if the alcohol is actually running through this particular area here there's a special enzyme called cytochrome to e1 okay so we actually write it like this let's actually show this enzyme let's use the
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purple again here's this enzyme here let's actually draw a face let's put a face to the enzyme okay look at that dude he's all kinds of weird alright this guy right here is called cytochrome - e1 this is a microsomal enzyme super important because he can actually metabolize the alcohol so that's an important one to remember is that this cytochrome complex here within the located within the endoplasmic reticulum can actually break down this alcohol and convert it into another molecule and
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that molecule is called a Seeta aldehyde and this dude he is bad news bad news bears this guy okay now if this guy this alcohol reacts with the cytochrome 2 e1 the cytochrome complex 2 e1 converts it into acetaldehyde that's one mechanism the other one the more common one the one that results in the large amount of this activity here is called let's do this guy in blue here actually is doing orange because it's an important one it is called alcohol dehydrogenase which we represent as ADH
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please remember this is not the ADH that you guys think about whenever it's responsible from the post HIPAA to eteri it's not this same one it says alcohol dehydrogenase this guy he can actually work in this step here and he can metabolize this alcohol and convert into acetaldehyde there's one other one okay another one that is also crucial in this process here and this is going to be another enzyme look at this dude let's actually draw him like this here's his little
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foot here here's his nose his eyes he's got like a little faux hawk going on there and he's got his arms in this reaction here this enzyme right here super important in this process also he is called catalase now some of you guys if you guys know a little bit about your organelles catalase is actually a very particular enzyme found in certain types of organelles what are some of those organelles that contains this guy they are peroxisomes so this also this alcohol can be metabolized by
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peroxisomes peroxo somes and again these peroxisomes contain this particular enzyme here called catalase and when the catalase reacts with alcohol it can convert that alcohol into acetaldehyde now one of the things that you need to remember and this is where a lot of the damage comes from drinking lots of alcohol so remember that next time you guys to think about drinking a lot right from this particularly from this system from the cytochrome 2e1 to really bad things happen here one is
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because of the cytochrome system it can generate a lot of what's called reactive oxygen species so they call them reactive oxygen species what are some of these bad boys just a couple I don't want to go over like too crazy some of them could be like hydrogen peroxide super toxic one right that's one really really bad one another one is your superoxide anion your superoxide another one could be hypochlorous acid another one could be the hydroxyl radical we talked about that that can react with
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copper and it can actually be the result of copper and iron where they undergo defense and reactions so some of these are super super dangerous now why are they dangerous you know what these reactive oxygen species love to do they like to donate their little random little loner electron and when they do that when they donate some of those electrons they donated two very crucial molecules inside of our cell what are some of them look here this guy you guys better know which one this one
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is right away DNA and not just DNA but it can even be RNA but DNA is one of the really bad ones because if these reactive oxygen species come over and damage the DNA what can it do produce mutations what happens if you have mutations they can lead to cancer so again that's one of the really really dangerous things here is that these reactive oxygen species can come over here and go by BAM they can start really laying some damage down on the DNA what else they can lay down some damage on
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certain types of enzymes that are crucial a lot of these different processes within the body so here let's make a little enzyme dude okay look at this guy he's okay now but guess what once he gets a lot of these different reactive oxygen species on him what happens but over the Valen alright he gets all freaked out too all right so that's really really dangerous here when these reactive Oh should be she's accumulate due to excessive alcohol consumption they can cause a lot of DNA
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and protein damage so we can lead to a lot of DNA and protein damage super nasty stuff right and we'll talk about something that the liver actually synthesize that is crucial to preventing that that you again you can thank the liver for kin what else is another negative thing about having too much alcohol consumption if there's a lot of alcohol consumption not only do you produce a lot of reactive oxygen species because of increasing this pathway but there's a crucial molecule here called
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na de positive look at this guy just chillin doing his little thing here but there's so much of this reaction that you're generating a lot of NADH s why is this bad here let me tell you let's come over here so we have plenty of room if we have lots of NADH s what is it takes it to the electron transport chain the electron transport chain generates a lot of 80p so now let's follow this high nadh leads to high ATP activity so now go back and think about the krebs cycle so let's say here I have
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my little TCA cycle or my Krebs cycle here we'll put TCA cycle the same thing as krabs remember that and who was feeding into it acetyl co a he was feeding into this and if you remember there was a lot of different enzymes that were allosteric lis regulated by ATP so if ATP levels are high what is that telling our TCA cycle to do stop so it's going to inhibit a lot of this TCA cycle activity and instead it's gonna drive the acetyl co ways into fatty acid synthesis Oh Oh
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a lot of fatty acids guess what that can do lead to a lot of fatty liver and so again what can this produce as a result it can produce a increase fatty liver okay so that's not too good either alright now just to finish off here the acetaldehyde how is this relatable so how does this alcohol cuz it actually counts for about actually comes for about seven seven kilocalories per gram so seven kilo calories per gram more than carbohydrates and proteins so I can
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get fat with these bad boys here right so acetaldehyde he can go and he can react with something else two things actually he's not a good he's not a good man he can get converted into acetate you know what asked to take can be converted into let's follow us down here react this bad boy with a specific molecule Co a so take here and add on a coenzyme a and guess what you get when you take the acetate and combine it with that you get acetyl co a and again lots
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of alcohol can lead to a lot of seat of CO a that can just continue to shunt into forming fat or it can be utilized to make a little bit of energy if necessary here's the last thing about with the acetaldehyde the acetaldehyde it can do something else it actually is kind of like a chain if you want to think about it it really binds on to something and just makes everything nasty let's say here again I have some type of let's put here let's just put here a little happy face okay
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this guy's happy some type of macromolecule let's just assume that it's a protein let's assume that it's a protein when acetaldehyde comes over here look what he does so I'm gonna represent him with a name he binds on to this guy when he binds on to this guy guess what happens when plant okay he becomes sad because guess what's gonna happen with this we can take this and we call this whenever I see the aldehyde binds on to a macro molecule like maybe a protein it forms what's called a duct
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and a cita aldehyde a duct guess what he can do with that he can take and present that our hepatocyte scan take him present i'll say that here's the cell membrane here's going to be a a protein let's actually do it like this we can take that and represent that acetaldehyde addict out here and then what will that do that'll activate our immune system guess what it'll activate it'll activate a bunch of different types of lymphocytes to come to the area so now we're gonna
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have a bunch of lymphocytes coming to the area and we might even have a lot of neutrophils coming to the area and this can lead to a lot of damage okay because there are gonna attack our own tissues so that's one of the negative things about this is that one thing is it can be presented on the cell which can activate our immune system another thing is when it binds to this actual macro molecule that macro molecule no longer can function so let's actually just do decrease in function
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well let's actually do this loss of function so now whatever that macromolecule is he can't do what he wants to do thankfully our liver is so kind to us and it does something so cool that can help to prevent a lot of this reactive oxygen species damage now we talked about him a little bit here was the glutathione glutathione is actually very very important in our liver you know what it can actually do here let me let me tell you what it can do let me move this
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fatty liver over here increased fatty acid synthesis again we said that can lead to a fatty liver okay so just to keep that there now the glutathione it exists in two forms okay so let me put it like this I'm gonna put G here that's a glutathione molecule usually it's in what's called a dimer form so in other words one form as it has let's say has this thigh all group here okay the other form is the glutathione is in a disulfide bond oh now it can go back and
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forth between these two so look it can go here or it can go back to here now the glutathione is a very very important antioxidant so what is this G representing it is glutathione super important antioxidant inside of our liver we're generating tons of reactive oxygen species all the time what this glutathione does is let's pretend we take hydrogen peroxide let's take hydrogen peroxide the glutathione has the ability to take that hydrogen peroxide or other reactive
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oxygen species and convert that into less toxic forms let's say like water in this case now what we what happened the glutathione actually took on some of those electrons okay and when it did that it actually got oxidized so this is the reduced form this form here with a thiols this is the reduced form and this form is the oxidized form when he reacts with the reactive oxygen species he goes into the oxidized form he sacrifices himself but guess who we have coming to our rescue to help us out
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so so much in a deep eh NADPH where did we get that from the pentose phosphate pathway he can be converted he can drop off his hydride ions onto the glutathione and he can Curt divert into nadp+ but when he drops those hydrides and electrons off he converts the oxidized glutathione back into the reduced which helps to continue to decrease the reactive oxygen species so be thankful for that glutathione and our liver has a bunch of it okay iein engines in this video we talked a lot
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about xenobiotic metabolism I hope it made sense I really do hope that you guys enjoyed it and ah another lecture we're gonna talk a lot about biosynthesis and a super super important because it goes hand in hand with xenobiotic metabolism so I really hope to see you guys in that video iron engineers if you guys did like this video please hit that like button comment down the comments section and please subscribe also if you guys get a chance go check out our Facebook or
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Instagram maybe even our patreon account as always engineers until next time
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