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Cytochrome P450 (How do I make drugs work?)

Discussion in 'Pharmacology' started by DavidJS, May 12, 2008.

  1. DavidJS

    DavidJS Newbie

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    Hi,

    My name is David; I'm a 31 year old who is suffering from a chronic pain condition known as Ehlers-Danlos Syndrome. A problem with collagen synthesis gives me hypermobility and elastic skin, and I suffer from Fibromyalgia and joint pain, daily. I also have gene duplications of CYP2D6 and CYP2C19; as well, my serotonin transporter is in the s/l form. I'm sick of drugs not working, and I want to see if I can figure out if there is anything I can do. I can take 12 tabs of Ecstasy and it's like a cup of coffee. I can take 15 OxyContins and it's nothing more than candy to my body. Marijuana barely works, and at 5'4" weighing only 120 pounds, I can drink everyone under the table. I tried magic mushrooms for the first time last night; 4 grams did absolutely nothing to me. People think it's great I'm "immune" to drugs, that I don't even have the option to get high or stoned; but, I also don't have an option for pain relief.
     
  2. radiometer

    radiometer bananadine addict Platinum Member & Advisor

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    With all due respect, this sounds like something to discuss with your pain doc. They should be well interested in making sure that your treatment is effective and, more importantly, safe.
     
  3. DavidJS

    DavidJS Newbie

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    I'm not under a doctor's care. I have 30 years of experience that makes me trust my ability to look after myself more than any doctor can. I have to research this on my own.
     
  4. Paracelsus

    Paracelsus Platinum Member & Advisor

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    It's less a matter of looking after oneself than a matter of expertise and medical responsibility.
     
  5. DavidJS

    DavidJS Newbie

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    I diagnosed and treated myself for a rare disease. No doctor was able to do that. Now, I figure things out on my own. I won't let a doctor come near me.
     
  6. Laudaphun

    Laudaphun Gold Member

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    Ok, you have SWIM confused. SWIY states here that they are 31 years old, and that SWIY has 30 years experience diagnosing oneself:

    Do not take this the wrong way, SWIM is just trying to get some facts straight so that she can make better sense of what SWIY is saying. Why does SWIY continue to experiment with all of this stuff at very high doses if it has never worked before. Duplicate genes alone wouldn't account for such resistance to these substances. Also, SWIY must be very intelligent if able to diagnose oneself for such rare diseases, assuming availability of the appropriate equipment. So this may sound dumb to SWIY if but has SWIM ruled out environmental factors? Environmental pollutants are capable of inducing P450 enzymes... for example polycyclic aromatic hydrocarbons. Also Polychlorinated biphenyls which were once very commonly used as insulating agents and plasticizers also induce or speed up the metabolism of some drugs. Has SWIY ruled out these possibilities when diagnosing oneself? Appologies if that is taken the wrong way. The 2D6 enzyme is a highly polymorphic and as such often varies considerably from individual to individual. Some have a complete absence of action, while others have ultra-fast metabolism. However, only a small (but significant) percentage of those displaying ultra-fast metabolism actually had duplicate genes, but the presence of duplicate genes is not really necessary to display the resistance to the drugs it would metabolize due to it's strong polymorphic potential.

    SWIM is assuming that all of this is based on self-diagnosis as SWIY has stated, due to the inability of the medical community to figure out what is wrong with SWIY. Well, that's terrific that you were able to work towards some answers. However, take that knowledge and present it to medical professionals, specialists, or whoever. Tests can be done to prove the presence of duplicate CYP2D6. Maybe the doctors you've saw before couldn't figure out what was wrong, but if SWIY has figured out what is wrong and can point them in the right direction then tests can be performed and then maybe they can help. SWIY is getting into genetics and with additional medical complications on top of that, there really aren't going to be many people out there that can help, as it is very complicated and involves some very specific disciplines. But, there ARE people out there that can help and SWIM suggests you seek them out, be persistant, don't give up. If SWIY has accurately (or even paritally) self-diagnosed themselves then that is a huge step. Present that to medical professionals, so that tests can be performed to verify some of these things, and then perhaps SWIY will find that then a dr. CAN help. Probably not a regular one, but some sort of or combination of specialists.

    When SWIM initially read the topic, she was excited as she is currently researching P450s as it is a topic of particular interest to her. However after reading the post, there isn't really much SWIM can help with.

    Finally, and this is not meant in disrespect or argumentative, just curiousity SWIY says in the last post:
    If SWIY diagnosed AND treated SWIY, then what is SWIY looking for here? SWIM is inclined to think that the title of the thread sort of suggests that while maybe SWIY was able to diagnose oneself, SWIY has NOT been able to effectively implement a treatment or more simpily self-medicate. SWIM is very passionate about this stuff and wishes she could offer help, but with all honesty, at this point in time the combination of complications SWIY presents is beyond SWIM. It is worth mentioning that SWIY has provided SWIM with some additional avenues to explore in her own research.
     
    Last edited: May 13, 2008
  7. DavidJS

    DavidJS Newbie

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    That's a lot to absorb; but, lets see if I can clarify things... I diagnosed myself with Ehlers-Danlos Syndrome. The gene duplications of 2D6 and 2C19, as well, my serotonin transporter being in the s/l form were detected when I had a Cytochrome P450 test done at The Mayo Clinic. So, I guess that means I'm in that small percentage that genuinely has duplicate genes. I'm treating myself for Ehlers-Danlos through diet, vitamins, minerals, and supplements; but, I don't have anything good for pain. If I were to take 100 Tylenol/codeine, nothing would happen. You don't know what it's like to be in the ER screaming in agony yelling at the doctors that they're not giving you enough morphine because it's not working. Or have surgery and keep waking up because the anesthesia won't keep you under.

    The reason I continue to take such high doses of drugs that don't work is because I'm trying to figure out if there's anything I can do to make them work. Maybe all it'll take is just a little more, or maybe a vitamin or mineral that's depleted in my body, that'll make the drug work. So far, I have had no success.

    I've been thinking the gene duplications could no way account for such a high level of tolerance, and maybe that's where my serotonin transporter being in the s/l form comes into play. I don't know. I can't seen to find anything that tells me what it means when your serotonin transporter is in the s/l form.

    DavidJS added 56 Minutes and 12 Seconds later...

    Here's what the Cytochrome P450 test says about me...

    Compound Heterozygous CYP2D6*1/*2A with CYP2D6 *2A Gene Duplication. This individual has a gene duplication of the *2A allele. This results in at least two copies of the gene that increases the amount of active enzyme produced. This individual also carries one copy of the *1 (normal) allele that encodes active protein. This genotype is associated with the extensive or ultrarapid metabolizer phenotype. This individual may not be able to achieve therapeutic drug concentrations, or adequate clinical response, using the usual drug dosage for drugs metabolized by CYP2D6.

    Homozygous CYP2C19*1/*1. This individual is homozygous for the CYP2C19*1 normal allele and has two copies of the gene encoding enzyme with normal activity. This genotype is associated with the extensive metabolizer (normal) phenotype.

    This patient is heterozygous for the short/long promoter polymorphism of the serotonin transporter gene. The short promoter allele is reported to decrease expression of the serotonin transporter compared to the homozygous long promoter allele. The patient may have an increased time to response with selective serotonin reuptake inhibitors due to the presence of the short form of the gene.
     
    Last edited: May 13, 2008
  8. Paracelsus

    Paracelsus Platinum Member & Advisor

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    From the information you posted, CYP2D6 duplication means ultrarapid metabolism, yet CYP2C19 duplication means nothing (extensive/normal metabolism). And CYP2D6 is not involved in the metabolism of morphine. Interestingly, CYP2D6 ultrarapid metabolism normally increases the activity of codeine significantly.

    The point is, your situation seems rather complex and paradoxical. Doctors may not know everything, but they do know quite a bit, and can refer you to further tests that will give you more information.
     
  9. DavidJS

    DavidJS Newbie

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    I took 100 Tylenol/w codeine a day for 8 years and my liver is fine; so, the Mayo Clinic doctor didn't believe me. I was in pain for 30 years, and all any doctor needed to do was believe I was I was telling the truth. The only way I'd goto a doctor about this is if I had something to go on. If whatever is going on is that complex, then I need a theory to present to a doctor. Otherwise, I know where this will go.
     
  10. Laudaphun

    Laudaphun Gold Member

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    just the simple presence of a duplicate CYP2D6 genes does not mean anything due to it's highly polymorphic properties. The reason being is that for as many people who have fully functional duplicate genes, approximately as many people have duplicate CYP2D6 genes that are mutated null allele genes which are inherited meaning that they almost completely lack CYP2D6 enzyme activity and have exactly the opposite problem that SWIY has.

    The problem is the fact that it mutates, and if gene duplication events take place then if it has a fully functional allele you have a problem similar to what you describe. But if able to figure out all this on your own, SWIM probably didn't tell you anything you didn't already know.

    However, the medical world does not stand still. "Until recently, detection of multiplicate CYP2D6 genes required the use of restriction fragment length polymorphism (RFLP) analyses."

    How long has it been since SWIY gave up on doctors?

    About 10 years ago "more simple and rapid PCR-based methods for efficient genotyping of UMs were developed." UM = ultra-rapid metabolizers (whether it be by mutated gene, duplicate gene, or whatever.

    Identification of people who have would be classified as an "ultra-rapid metabolizer" is very very important for adjustment of doses in drug therapy, as well as to avoid misidentification of noncompliance.

    Tests can prove this! Ask for the tests to be performed, then you would have conclusive evidence that you are in fact telling the truth. SWIM thinks your doctors would definitely work with you if you can document this condition.

    Also as stated in the above post, 2C19 would have only considerable inducing effect on diazepam, naproxen, nirvanol, omeprazole, propranolol, and S-mephenytoin. But diazepam itself has an active metabolite, nordiazepam which accounts for it's longer half life. So an inducing effect on diazepam would not necessarily reduce it ineffective. And also 2D6 induces metabolism of codeine as also stated in the above post which is this particular case is a good thing as the faster and more rapid metabolism of codeine, the more of it would be converted to morphine compared to a regular person. As far as the MASSIVE amounts of acetaminophen SWIY consumed via the 30mg codeine/ 300mg APAP and no liver damage after 8 years... acetaminophen is metabolized by 1A2, 2E1 and 3A4 and to a lesser extent 3A5... Actually it is 3A4 that accounts for metabolism of over 50% of commonly prescribed as well as THC.

    again you are confusng SWIM. Explain please how SWIY can be 31 years old and have been in pain for 30 years? Do you remeber being 1 years old? Again not trying to argue but can you explain how this is so? Was SWIY born into this world and immediately needed to be treated for pain? That can be the case perhaps, but I don't know many people that can remember being 1 year old. Just trying to get to the bottom of this and some answers to some questions.
     
    Last edited: May 14, 2008
  11. DavidJS

    DavidJS Newbie

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    30 years was just rounding up. My legs began hurting when I was 5 years old, so 26 years, to be exact. It's due to a genetic disease I was born with. But, I do have memories going back to 2 months old as my mind seems to operate much differently than everyone elses. I found a description of the way my mind works; some sort of rare condition called Hyperthymesia. My memories don't fade, and I don't just remember my life, overall; but remember the individual days.

    >Tests can prove this! Ask for the tests to be performed, then you would have conclusive evidence that you are in fact telling the truth. SWIM thinks your doctors would definitely work with you if you can document this condition.

    I have had the Cytochrome P450 test done by The Mayo Clinic and have documentation showing I am, in fact, an ultra-rapid metabolizer.

    >The problem is the fact that it mutates, and if gene duplication events take place then if it has a fully functional allele you have a problem similar to what you describe.

    Is this what you are talking about?

    Compound Heterozygous CYP2D6*1/*2A with CYP2D6 *2A Gene Duplication. This individual has a gene duplication of the *2A allele. This results in at least two copies of the gene that increases the amount of active enzyme produced. This individual also carries one copy of the *1 (normal) allele that encodes active protein. This genotype is associated with the extensive or ultrarapid metabolizer phenotype. This individual may not be able to achieve therapeutic drug concentrations, or adequate clinical response, using the usual drug dosage for drugs metabolized by CYP2D6.

    >How long has it been since SWIY gave up on doctors?

    It has been 4 months.
     
  12. RoboCodeine7610

    RoboCodeine7610 Silver Member

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    I'm sorry but that's just impossible...That would be more than 30000mg of Paracetamol, and you would surely have died if it were true...
    Personally, I think you're full of shit, but that's just my opinion...
    Sorry if I was rude, but i just couldn't avoid saying it.
     
  13. fiveleggedrat

    fiveleggedrat Palladium Member

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    Has Swim ever contemplated speaking to some sort of medical/drug researchers on this matter? Or at least some sort of specialist?

    Swim sees how going to GP's and such would be absolutely useless.
     
  14. RoyBatty

    RoyBatty Silver Member

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    Wow!!

    I don’t know what to write, I’m lost for words ...

    This thread got me interested as soon as I started reading it yesterday. I know quite a bit about subjects like this (not wishing to blow my own trumpet); so I did a quick bit of research on statistics etc.

    The s/l form of SERT is nothing out of the ordinary.
    Being homozygous for CYP2C19*1 isn’t rare, or even uncommon.
    The gene duplication of CYP2D6 *2A isn’t that uncommon, especially in parts of Asian and Africa.
    Self diagnosed with the rare genetic disorder Ehlers-Danlos Syndrome!
    The incongruity of CYP2D6 ultra-rapid metabolism with codeine!

    If alarm bells weren’t ringing before, by now my head is in Big Ben.

    I decided to find out more. This is a quote I found:

    “I ended up being sick with Ehlers-Danlos Syndrome; but, then I wanted to research some paranormal like abilities that I seem to possess. I ended up getting busy and then dropping the ball for a while; but, when I picked up the scent again, it led me to who I really am. I am an Indigo. I was also born with the healing powers of a Shaman. I was never sick with Ehlers-Danlos Syndrome, either. That discovery was an accident. I have that disease; but, it doesn't affect me; it's completely blocked by the quantum energy. However, I was experiencing the revival of childhood ailments, which in me, would have been EDS related. I was going through the process of Ascension.

    This is all so surreal to me. Suddenly, I can heal people by placing my hands on them or gently blowing on them. I can think traffic lights green. I can stop the roulette wheel on my number. The most amazing thing is... I can control the weather. If I get upset, a dark storm cloud appears over my head, continually growing in intensity until I cheer up. If I'm in my car, it'll literally follow me around the city.

    I'm even receiving messages. I will always see the same number sequences on license plates, and I'll always look at the clock at the same time as those number sequences. I also see a lot of the same letter sequences on license plates. The only thing is, I don't know how to decipher them. I'll think I'm onto something, but then I really don't know if I'm even close to the right track.”

    RoboCodeine7610, it appears you were right.

    Roy