2.4 – What is a patient? Variation in disease resistance

as we saw in the last lectures as humans spread out across the planet they encountered different diseases and that resulted in genetic variation for disease resistance but they also encountered different diets that contained different nutrients and different toxins as a result patients very genetically in their ability to metabolize drugs because of their recent evolutionary history the area of science that studies this is pharmacogenomics and its idea basically is to analyze how much does individual human genetic variation affect our ability to metabolize drugs it arose because we got a very serious signal in the late 1950s an anti-diarrheal drug called Cleo Qin all was tested and found safe on Europeans and then without testing it on Japanese it was released in Japan and it killed some hospitalized many possibly an interaction with environmental problems in that post world war ii environment but very likely primarily because the Japanese differ genetically from the Europeans individual and inter-ethnic variation in cytochrome p450s these are called sips and in an acid sealed transfer aces in 1977 in 1953 in both cases that was initially found through adverse drug reactions so patient suffers and people wondered why and did detective work now we have information on human limb genomes and that's being used to find alleles and to predict variation in drug response using more sophisticated computer modeling techniques the same gene products that metabolize drugs are also involved in processing toxins and food in fact that's why they initially evolved and they process smoke and on the byproducts of other carcinogenic substances and are thus involved in the mechanisms that he licit cancer and shape the revolution of its resistance to drugs so this is not just about how well the patient's process drugs it's also about how likely are they to get cancer and if they get it how likely are we to be able to treat it now patients vary in their drug response for many of reasons and only some of those reasons are genetic so they vary in drug response because they are different ages genders ethnic background weight family history what the time of day affects it their microbiota affect it and also there can be placebo effects those are clinical reasons and then in the environment it depends on how well nourished they are what other drugs they might be taking because there are drug drug interactions there are chemical exposures their lifestyle whether they are a drinker or smoker and how compliant they are all of these feed together to produce a particular dynamic or kinetic of the drug in the body and that leads to a particular intensity and duration of drug response which can have a therapeutic effect and can also produce an adverse reaction or toxicity there are two main classes of enzymes that are involved in drug response the first of which are the cytochrome p450s these are heme thiolate proteins and their significance in processing toxins and now drugs is indicated by the fact that these are families of genes that exist in many copies and they evolve by repeated duplication they are proteins that are bound to a heme group and their color and their absorption peak which is about 450 nanometers give them their name that's why they're called cytochrome z' in humans we have 57 of these genes they are bound to the endoplasmic reticulum and to the inner mitochondrial membrane they mediate our response to toxins and to steroids as well as other reactions there are 23 genes in the first three families and they account for about 75% of human drug metabolism we're going to focus just on one of them it's called sip 2d6 cytochrome p450 2d6 this is what a representative cytochrome looks like it has two heme groups here and here and life is using these heme groups to manipulate oxygen precisely so you can think of cytochrome p450s as being surgical specialists in dealing with oxygenation reactions which in chemical formula look like this you'll have some molecule and you can add in the presence of a cofactor and oxygen to it you can then produce hydroxyl radical and water now cytochrome p to d6 is clinically important because of its variation it was discovered in a case in London in 1977 there was a volunteer who had a hypotensive response so low blood pressure too deep de bris a'queen that's an antihypertensive and then another volunteer and Vaughn had increased side effects taking sparking which is anti-arrhythmic so both of these were related to variation in sip to d6 it is now known to be involved in adverse reactions or decreased drug effects for many drugs anti-arrhythmic s– antidepressants Durell lept –ax anti and giles opioids amphetamines and anti-cancer drugs like tamoxifen so this is an extremely important mediator of the patient's ability to respond constructively to drug therapy the percentage of poor metabolizers you know the jargon in in this area of science is a p.m. for poor metabolizer very strikingly among ethnic groups so here's some ethnic variation and sip to d6 the ones here in this gray region are not functional basically what you can see here is that people who are of african-american ethnicity most of them have a much higher frequency of allele 1 than do people of East Asian ethnicity and American whites also share that with Africans however other Europeans have lower frequencies of that then do East Asians so there's quite a bit of ethnic variation and and the point here really is individual humans differ tremendously in the probability that you'll have a variant of this particular enzyme now why is that important well it can vary from two to three copies per individual it metabolizes about a quarter of all of the drugs on the market its polymorphisms influence about twelve to fourteen percent of all drug metabolism and that includes antidepressants anti anti cancer drugs and analgesics duplications reduce the efficacy of drugs that treat arrhythmia Alzheimer's and heroin addiction but they improved tamoxifen treatment of breast cancer as a result of those facts the drug industry now tries to avoid developing drugs that are metabolized by this enzyme because they cannot predict how individuals will react to it it has a direct impact on drug rehabilitation to other cytochrome p450s 3 a 4 and 2 B 6 have variants that cause great very individual variation in how much methadone you need to give a patient to achieve a given blood concentration of that drug to obtain a methadone plasma concentration of 250 nanograms per milliliter a dose of methadone as low as 55 milligrams per day or as high as 921 milligrams per day can be required in a 70 kilogram patient that's more than 16 fold variation in dose and it's caused by variation these genetic polymorphisms it depends on which of those genes that particular patient has there is another very important set of enzymes that are involved in drug metabolism and those are the NS a teal transfer aces there are two of them an 81 and an 82 they activate and deactivate both drugs and carcinogens and they are active mostly in the liver cytosol so they are part of the metabolic machinery that makes the liver such an important part of cleansing our body different alleles combine to produce rapid intermediate or slow Isetta later phenotypes they were discovered in 1953 in patients who were being treated for tuberculosis with a drug called isoniazid the drugs that they metabolize include sulfonamides many other drugs and the metabolites of caffeine so people vary in their reactivity to coffee and tea because of genetic variation in an in a sealed transfer racism Europeans and North Americans are about 22 to 26 percent fastest settle eaters and East Asians are 67 to 74 percent fastest elevators so ethnicity is giving an indication but not a precise read on the probability that a patient will be either a fast or a slow Isetta later this is what that molecule looks like it's movable parts are in red that indicates the the part of the molecule which is going to be adjusting to the substrate there is important genetic variation associated with cancer susceptibility there are two major associations one is that the impact of an environmental toxin on cancer risk depends on which genetic variant one has for an acetyl transferase and the other is that the ability of a cancer clone to resist chemotherapy depends both on the genetic variant it inherited from the germline and shares with the other cells of the body also on what somatic mutations it has acquired during the development and the clonal evolution of the cancer here are a few examples of how n acetyl transferases interact with the environment to determine cancer risk for bladder cancer the N 82 slow acetylene Isetta laters are about one and a half times more likely to get bladder cancer and those that have a combination of na to slow with na T fast and current or ever cigarette smoking are nearly three times two point seven three times more likely to get bladder cancer so here the interaction effects between the genes and between the genes in the environment are both important for colorectal cancer one of the most important cancers that hits people as they age an eighty one fastest settle eaters have significantly higher risk of colorectal cancer than did the slowest centiliters and smoking intensity increased colorectal cancer risk among carriers of both na t1 and a ten eighty two fastest centiliters for pancreatic cancer one of the nastiest cancers and one that can produce devastating metastasis na t1 polymorphism interacts with dietary mutagen in intake and increases the risk about 2.2 to 2.5 times and it does so in men but not in women so you can see that the genetic variation is interacting both with environment and with gender to produce different profiles of cancer risk both because these molecules are involved in detoxification of things that could induce cancer but also because these molecules are involved in how well the cancer cells themselves can resist chemotherapy there is also genetic variation as I've mentioned to chemotherapy so all cells in the cancer share the genetic capacity to process drugs with the abilities that the healthy cells in the body have and so patients can begin life with different potential responses down the line to chemotherapy for reasons they inherit from the germline however cancer cells also accumulate many somatic mutations some of which may affect their ability to metabolize drugs and thus to resist chemotherapy chemotherapy applies very strong selection to competing clones and it rapidly selects resistant clones some of that resistance is probably attributable to mutations in the genes that are coding for cytochrome p450s and in assets he'll transfer aces we can use genome-wide Association studies G was to discover genetic variation for adverse drug responses here it seems to work pretty well and seems to explain a bit more than we can when we use G was to explain disease resistance the reasons for that are not yet well known and what we can see is that if you have a clinical problem like Myo toxicity and the drug involved is a statin in this case in the statin then G waz has found a particular gene where variation is influencing that particular reaction this is also true for efficacy of treatment to a viral infection for treatment with Anik or Nanuk anticoagulants and for others so the point is that we now have fairly good high-tech means of identifying particular genes whose variation is associated with adverse drug response and that gives us hope that in this particular part of medicine identifying individual variants is going to bring a clinical payoff so to summarize individuals vary in the alleles the process drugs and environmental chemicals if they cannot process a molecule rapidly enough it will build up and can act as a poison cancer cells also vary in their susceptibility to chemicals this accounts for some of the evolution of resistance to chemotherapy knowing the genetic constitution of an individual and of individual cancer clones can improve treatment outcomes and can reduce treatment risks

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