CYP2D6 ability to metabolize tamoxifen and recurrence

Live, they received my sample back on the 20th of July... and told me I'd have it Wed (exactly 2 weeks later). Have you called them? They are very helpful and will give you updates. I've called them 4 times in the last two weeks just to check. I was a little anxious.

wow... ladies, this report is AMAZING.. I have 24 pages of all the types of medications that I should use / avoid based on my pathways. This Complete Gene test was only $149, and I'm Thrilled with how detailed it is... And these 24 page report is only 1 of 8 that I have been given. I have a TON of info to sift through.

My MO just prescribed me Effexor and after reading this, I am hesitant to take it! Anyone else have any opinions? I am on tamoxifen and very concerned about a possible interaction, even though my MO says Effexor is safe.

I purchased a subscription to a medication database for 7 days and then published the full list to all the drug interactions for Tamoxifen which is here: https://community.breastcancer.org/forum/78/topics/846316?page=1#idx_8

With Tamox, Effexor (Venlafaxine) is considered a D rating: Venlafaxine is a Try to Modify and find replacement drug. It's not an X, but a D rating is one you want to consider not using.

Keep in mind there are TWO points to consider... 1) is if it's on the medication interaction list I just published. and 2) is if you are like me and have issues with your Enzyme metabolism. I'm a UM, so I am not supposed to have drugs that utilize the CYP2D6 pathway as a non-prodrug. Effexor, and it appears nearly all of the antidepressants are no go for me just due to my metabolism. Tamoxifen is a prodrug, so it uses the CYP2D6 pathway differently than Effexor, so I actually should be able to do ok on Tamox (but may have increased SEs).

Also if you are a poor or intermediate metabolizer, by taking another drug using hte same pathway as Tamox, you are creating competition for the enzyme, so your body might not get enough Tamox.

Obviously, medication databases aren't going to discuss these because they are so individualized. One woman may be able to take Tamoxifen and Effexor just fine and another woman will have issues. I think following their D rating guideline is the way to go: Try to modify...

Lisey, I wish I knew what the list of numbers and letters mean in your test result. What I get from *1xN is that *1 was the duplicated allele but beats me how many copies you had or what it means. I can only say what I would do. If I was tolerating tamoxifen well like you are, I think I would keep taking it and monitor endoxifen level and for more serious side effects (blood clots, abnormal vaginal bleeding and thickening of the endometrium, eye and heart rhythm problems). A lot of us are taking low dose aspirin and/or fish oil to prevent blood clots (I take both). Vaginal ultrasound can be used to monitor your uterus, and you should feel any heart rhythm issues, but maybe an occasional EKG to make sure it doesn't give you long QT. Regular eye exams.

I still intend to do some more reading because I would like to know what the evidence finds in total since it often conflicts, but from what I have seen from looking quickly, UMs should be OK as long as they can tolerate the side effects. Some studies have shown a connection between side effects and endoxifen level/effectiveness, but others have shown the opposite. There was one that found IMs and PMs to have the most side effects - which wasn't my experience - so I don't think side effects are a good indicator for everyone. They could still show up though the longer you take it.

Here's what YouScript says about tamoxifen and Effexor:

Effects

Coadministration of multidosed venlafaxine and multidosed tamoxifen resulted in slightly decreased tamoxifen metabolite (endoxifen) plasma concentrations ^1,2,3.

Management

Venlafaxine is considered the safest antidepressant for treatment of flushing or depression in patients coadministered tamoxifen ³.

Evidence

High

Btw, I noticed in the 2009 study I posted above, that Desvenlafaxine is not metabolized via the P450 system. So, that might be an alternative to Efflexor. I know nothing about how they all compare, but it might be worth asking about.

I gotta say, Lisey, that is an amazing amount of information you got from a $149 test! I'm thinking everybody who takes medication should be getting it. I'm really considering getting it done, too.

By the way, another thing on the report.. I'm a COMT met/met variation... so that means certain dopamine drugs don't work on me.. I googled what the COMT met / met does and it's amazing... Apparently it's an evolutionary twist of met.. the normal is 'val/val' and most people are either val/val or val/met... The fact I'm met/met means I have a naturally high level of dopamine and it floods my brain constantly so I'm always 'on' and thinking.. (true).. Here's a really interesting article on it. All this in the little Kailos test... amazed!

______________________________________________________________________

Two years ago, the NIMH researchers reported that people with theval/val variant had evidence of reduced prefrontal dopamine activity and less efficient prefrontal information processing, along with slightly increased risk for schizophrenia. People with val/met had more efficient prefrontal function, and people with met/met the most efficient. The met variant results in 3-4 times weaker enzyme action, which is thought to allow for more dopamine activity in the prefrontal cortex, as the neurotransmitter breaks down more slowly.

Since amphetamine boosts dopamine activity in the prefrontal cortex, the researchers predicted that the drug would, in effect, correct a deficiency in people with val/val—that they would experience more optimal levels of dopamine and perform better on working memory and other cognitive tasks known to depend on the prefrontal cortex. They further predicted that people with met/met on amphetamine would perform worse and their frontal lobes would function less efficiently as task difficulty increased.

http://www.nimh.nih.gov/news/science-news/2003/gene-enhances-prefrontal-function-at-a-price.shtml
https://neuroamer.wordpress.com/2012/06/29/card-sorting-pot-smoking-happiness-and-one-gene-comt-catechol-o-methyl-transferase/

Ok, I just need to add. this goes even deeper ladies. COMT is a huge thing.. apparently both val/val and met/met varieties have an increased risk for breast cancer - but different types. met/met = ER+, val/val = ER- (met/met's are considered low activity COMT.

and COMT has a huge factor in Estrogen removal. I'm a low COMT (met / met) so I'm not able to remove the Estrogen like val/vals (high COMT) could....

I went through this report below and I'm a met/met (A/A) to a tee... this is so weird having your personality explained by enzymes.

https://selfhacked.com/2014/12/24/worrier-warrior-explaining-rs4680comt-v158m-gene/_________________________________________________________________________________________________________________________________

Catechol estrogens form from CYP enzymes breaking down Estradiol and Estrones Catechol estrogens can break DNA and cause cancer and autoimmune conditions

COMT methylates (using SAM) and inactivates these catechol estrogens (2- and 4-hydroxycatechols)

The products of COMT methylation are 2- and 4-o-methylethers, which are less harmful and excreted in the urine (they have anti-estrogen properties)

However, if COMT is inhibited too much either because of genetics or dietary inhibition, it should result in higher levels of catechol estrogens, especially if glucuronidation and sulphation pathways are not working

4-Hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas 2-hydroxylated metabolites were without activity

4-Hydroxyestrogen can be oxidized to quinone intermediates that react with purine base of DNA, resulting in depurinating adduct that generates cancerous mutations. Quinones derived from 2-hydroxyestrogens are less toxic to our DNA

Estrone and estradiol are oxidized to lesser amount to 2-hydroxycatechols by CYP3A4 in liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a larger extent

It has been observed that tissue concentration of 4-hydroxyestradiol are highest in malignant cancer tissue, out of all the estrogens

The concentration of these Catechol Estrogens in the hypothalamus and pituitary are at least ten times higher than parent estrogens .

Catechol Estrogens have potent endocrine effects and play an important role in hormonal regulation (those produced by hypothalamus and pituitary)

Increased availability of estrogen and estradiol for binding and hypothalamic sites would facilitate the formation of Catechol Estrogens. These estrogens affect Luteinizing Hormone (LH) and maybe follicle stimulating hormone (FSH) and prolactin (R).

Catecholestradiol competes with estradiol for estrogen binding sites in the anterior pituitary gland and hypothalamus and dopamine binding sites on anterior pituitary membranes

Other possible mechanism of inactivation of these catechol estrogens include conjugation by glucouronidation and sulphation

High concentration of 4-hydroxylated metabolites caused insufficient production of methyl, glucouronide or sulphate conjugate which in turn results in catechol estrogen toxicity in cells and oxidation to semiquinone and quinone, which may reduce glutathione (GSH). These oxidation products could lead to DNA mutations

The quinone/semiquinone redox system produces superoxide ions (O2¯ ) which can react with NO to form peroxynitrite, which could cause DNA damage .

In summary, CEs lead to the production of potent ROS, capable of causing DNA damage, thus playing important role not only in causing cancer but also in systemic lupus erythematosus (SLE) and Rheumatoid Arthritis

The abilities of the estrogens to induce DNA mutations were ranked as follows:

4-hydroxyestrone (most damaging) > 2-hydroxyestrone > 4-hydroxyestradiol >2-hydroxyestradiol > > Estradiol, Estrone

Exactly Fallleaves!! I'm reading these things as well. My met/met (A/A) COMT means apparently green tea works on me much better than the average people (I hate tea, but am willing to try it.) They also suggest I take DIM to help compensate. I'm nervous about that as I don't want to mess up my Tamoxifen. Solfeo, can you check on if diindolylmethane (DIM) and Tamox are conflicted with your medication subscription? (mine ran out)

Honestly, it's like all the little pieces of my body were working in conjunction to give me cancer. I had a pituitary microadnoma for years as a young woman... it raised my estrogen up and they put me on meds... And everyone says I'm like super high on speed all the time (the results of my COMT gene A/A) That floods my brain with constant dopamine but can't eat the bad estrogen.

This test was the best thing I could have done.. it all is making sense now.

Here' the article on Green Tea and people with my type of mutation on COMT

There is substantial in vitro and in vivo evidence implicating tea polyphenols as chemopreventive agents against various cancers. In a case-control study conducted among Asian-American women in Los Angeles County, we reported a significant inverse relationship between intake of green tea and risk of breast cancer (A. H. Wu et al., Int. J. Cancer, 106: 574-579, 2003). Because catechol-containing tea polyphenols are very rapidly O-methylated by human catechol-O-methyltransferase (COMT), we are interested in determining whether the association between tea intake and breast cancer differed in women according to COMT genotype. We examined the interrelationships between tea intake, COMT genotype, and breast cancer risk in 589 incident cases and 563 population-based controls from a population-based case-control study of breast cancer in Chinese-, Japanese-, and Filipino-American women in Los Angeles County. Risk of breast cancer was influenced significantly by intake of tea, particularly green tea intake. However, the inverse association between tea intake and breast cancer risk was observed only among individuals who possessed at least one low-activity COMT allele. Among women who carried at least one low activity COMT allele, tea drinkers showed a significantly reduced risk of breast cancer (adjusted odds ratio, 0.48; 95% confidence interval, 0.29-0.77) compared with nontea drinkers after adjustment for relevant demographic, menstrual, reproductive, and dietary factors. This risk reduction was observed in relation to both green tea and black tea intake. In contrast, risk of breast cancer did not differ between tea drinkers and nontea drinkers among those who were homozygous for the high activity COMT allele (adjusted odds ratio, 1.02; 95% confidence interval, 0.66-1.60). In conclusion, tea catechins appeared to reduce breast cancer risk in this study of Asian-American women. Reduction in risk was strongest among persons who had the low activity COMT alleles, suggesting these individuals were less efficient in eliminating tea catechins and may derive the most benefit from these compounds

http://www.ncbi.nlm.nih.gov/pubmed/14612555?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Result%20sPanel.Pubmed_RVDocSum

Haven't looked here since July 21st. OMD(oh my dog). You gals have been busy. I got a headache reading the two pages. All I can say is CHIT(shit).

A couple of thoughts before I loose them.

Savella/ milnapricin is a SSNRI and doesn't go through the CYP system. Owned by Forrest labs with trade patent till 2021. BUT it's an old drug. Was used in Europe for 10 years when Forrest bought the rights in 2009. I used it for several years, but at a low dose. Only s.e. was I lost 30 ibs, very slowly.........that was a lovely s.e. The studies on it are very good. The more recent ones even better (this last decade).

My counselor got turned on to Genelex b/c he had a difficult drug management case. I had told him about Genelex. In exasperation he had her tested. Her 2D6 was absent. Which you all know most pyschotropics use that path. It explained the problem. He worked with the Genelex pharm doc. They put her on Zoloft Worked like a charm. It was an interesting session when he started off thanking me about telling him about CYP and Genelex. As a result he had all future patients tested before considering any drug recommendations. Not sure what he's doing now lost him b/c of Obamacare.

Lisey thanks for finding those posts. I was so insistent and now, I have lost interest. May look at it in the future, but appreciate your follow through.

I'm going to do the Ancestry.com thingy. The kit actually should be here soon. Then I think I'll get the kalios done. The 149$ one. Since my 3 of 6 tested were abnormal and tremendous incidence of cancer in the paternal side i.e 25-26 /53 blood relatives with 9 being BC. based on what ya'll have identified here it sounds like a good thing to do.

On the codeine conversion, if memory cell trigger is right take a look at the step in 3A4 to conversion to morphine.

There are lot's of viewings going on right now since this thread restarted. Which means you folks are getting lot's of other folks interested. Very good. Back away's someone asked why the docs aren't doing this more and I responded that they didn't know the CYP system. Said the same thing in the early pages. I think it is much more evident as you've learned so much since you've been here, that it's true. It likely will become a American Medical Association subspecialty. The whole system is just way to intricate and exploding with new info.

Eventually it will be done at birth or at first serious illness, but we are a few years away from that.

Lisey, I think it's you that has the high dopamine levels. Well, isn't that nice. The energizer bunny. Add to your study list as too how this impacts the cardiovascular system long term. You may actually have to figure out how to block it. Just a guess. Key in on two things 1. peripheral vascular system and kidney impact, and 2, cardiac muscle.You may have started that study already. If it plays out like I'm thinking, you will need blocking, but let me know. If you want the rest of my thoughts just say so, if you want to just do it on your own, I will wait.

Just as a small experiment go to the Beta blocker thread and read my latest posts on BP and pulse. Then keep a cardiac diary for a couple three weeks, but extend it to include pre and post exercise activity. It'd be interesting to see what your numbers are.

Have you done any reading on orgasms and dopamine? Maybe to personal, but if you feel comfortable talking about it, it would be interesting.

Lisey, I ran through some studies none of which brought forward anything close to what my thoughts were. So rather than play a guessing game, I'll just tell you b/c if there is research out there unless I give you the direct thing to focus on you'll be lost.

1. What is identified in the different combinations that you describe in your kalios workup may be so new that the overall implications to the cardiovascular system aren't known or are being studied now and publications haven't been done. As you know it take years to study something.

2. I'm going to take this in reverse and then get to the final thought that I think you need to consider. Dopamine is used in several particular cardiovascular states as the drug of last resort

..........Cardiomyopathy. That is an enlarged heart where the muscle is flabby and poor contractility. That leads to poor cardiac output. Poor cardiac output leads to low blood pressure. People don't do well with that. Google signs and symptoms of cardiomyopathy. Cardiomyopathy can run in families. Once a person reaches a certain level dopamine type drugs are used to support the cardiac muscle. These are given by infusion. The end result of cardiomyopathy is heart failure. Cardiomyopathy is one of the leading reasons for heart transplants

...........Don't panic, wait till I get to the end.

..........Dopamine is the drug of choice for peripheral blood pressure in septic shock. In septic shock the synapse that release the neurotransmitters that cause vasoconstriction fail. Early septic shock dopamine can help support vasoconstriction.

.......... Cardiogenic shock. There are several origins of cardiogenic shock. The key drug used to support the heart in cardiogenic shock is dopamine.

Now to you

3. The first question you need to study is "does the "met/met(?)" genetic person have a lifetime risk of developing cardiomyopathy?" Working on an analogy. Okay try this, If someone takes speed all the time, they will die in a pretty short time b/c the organs wear out b/c of fatigue. So, question two, if you have a lifetime of elevated dopamine levels, does that mean that eventually your organs wear out faster? Again don't panic because you just need to find the answer to the two questions.

IF my questions do show any long term connection, then at this stage a skilled cardiologist that understands the genetics can develop a plan. The plan would include baseline studies. It's a long list, but doable i.e labs, echo's, stress testing, maybe Thallium mapping. Then the next step would be a drug/lifestyle plan. Lot's of really good drugs for cardiovascular management. Then it would be a lifelong management and surveillance. All doable.

The real beauty of what you have done by your testing is, if there is a connection, you have identified a problem that you can work on preventing the long term consequences. Analogy, you keep the barn door closed. Generally, folks only become aware of the cardiovascular problems in the late or later phases. Analogy, the barn door was left open.

SAS, just back from a weekend trip. Read your words and wow....

Did you know I have continuous Low blood pressure? All the docs think it's great... but they always tell me I'm super low. AND When I get stressed from working, my feet turn purple and swell. Like SERIOUS purple if I'm standing/sitting too long. I was told I have Acrocyanosis - which is harmless. My feet aren't painful, but I've been calling attention to my feet and low blood pressure to docs.

Looks like I'll have to call the heart doctor.

Okay. seriously don't want t get into the neurosnynapse study but to completes the study here it must be done. CHIT

I know SAS and I are sidetracking... I apologize to viewers.. That Kailos Test has really opened windows into my body though.. especially the COMT thing....

SAS, don't wear out your neurons on my account... I totally agree that docs have not connected the dots on any of these genetics tests yet. But it's so amazing to me that the COMT met/met gene actually explains my personality and my purple feet! (not to mention my craving for Brussel Sprouts - which has the highest COMT out there by three times the amount to any other veggie). It's seriously one of the only veggies I like. I've been asking if my heart is ok for years because I'm healthy and the swollen puffy purple feet thing always bugged me. But the docs said you have 'some of the lowest blood pressure we've seen - that's so awesome!" (typically around 80-90 over 50-60). No one has said that the purple feet I get while sitting / standing (it goes away when my feet are up) is a troubling sign.

Not to mention that those people with Low COMT are less able to process bad estrogen.. which makes my body more susceptable to ER+ cancers from toxic ER+ in the environment. Oh... and I had a pituitary microadnoma for years in my teens and twenties. (my prolactin levels seem normal now so not sure what happened to it)... Add in the ER+ Melanoma 6 years ago... the pieces all fall into place.

I still LOVE how fast I process and how I have energy for days. People have described me as having a constant 'up' / manic state which exhausts them just looking at me. I personally get a ton of shit done! I'm working 12 hours a day and LOVE it... I'm able to accomplish so much and can never stop moving / creating / doing. I'm not really sad unless I have anxiety.. so yes there are shitty downsides to the dopamine flood... there's positives too.

I'm going to ask for a heart workup to see where I fall.