The CYP450 Medication, Inflammation, and Histamine Connection

I have been wanting to write for some time on the CYP450 medication, inflammation, and histamine connection, as this information has been so important in my own pathway to recovery.

My story

I have had histamine intolerance all my life, but developed mast cell activation disorder, when put onCYP450 mediated (and in particular CYP2D6 related medication).

Simplistically, I have CYP2D6 genetic mutation, which pushed my body into oxidative stress, that resulted in chronic inflammation markers (mine were c-reactive protein, and ceruloplasmin).

There are many paths to histamine intolerance and mast-cell activation disorder and my path is just one of them. Medication intolerances, however, are extremely common once firmly on that pathway.

There are a number of reasons why medication may be problematic with histamine intolerance, and I am only addressing one of them, which is the CYP450 medication, inflammation, and histamine connection

Histamine Mechanism

Histamine is an organic compound, produced by and stored inside tissue mast cells and blood basophils. There are two major mechanisms of histamine release – an active and a passive mechanism.

The active mechanism is evoked by an antigen-antibody response, such as an infection, which triggers the organised release of histamine from its granules into the tissues without cell death.

The passive mechanism, also known as cytotoxic, is evoked when a noxious stimuli, damages the cell membrane and everything stored inside the cell is released, including histamine. Histamine is released as the cell dies.

Whether active or passive, the integrity of the cell membrane, plays a major role in the release of histamine, and this is why mast-cell stabilising foods (and even medications) can be helpful.

Free Radicals

Free radicals are extremely harmful to the cell membranes, and provoke the release of histamines from mast cells and basophils. Studies show that free radicals interact directly with the cell membrane, eliciting an active release of histamine without actually damaging the cell. This is part of a complex sequence of events that occur at sites of inflammation.

Despite the fact that free radicals are known to be harmful to cells, they elicit an active (without cell death) release of histamines. This means that somehow receptors on the outer membrane, recognise these free radicals and provoke the organised release of histamine without cell death.

This may be physiologic, because when the body faces an infection, white blood cells produce free radicals to destroy bacteria, and the same free radicals elicit the release of histamine, which promotes blood flow to the area of infection, and triggers the calls for more white blood cells.

Prescription Drugs

Prescription drugs that are metabolised by Cytochrome P450 genes (whether you have a genetic mutation or not) have been shown to generate oxidative metabolites that act as free radicals. Other substances (such as some Omega 6 fatty acids) can also cause oxidative stress.

Several studies demonstrated that in mast cells, these free radicals can provoke the release of histamine, mostly through an active mechanism (that does not result in cell death but releases histamines as a protective response).


Studies show that if natural anti-oxidants, and in particular glutathione, is present in enough quantities, it can protect mast cells against free radical damage, and consequently halt histamine release. This suggests as a minimum that glutathione can improve the tolerance of medications, and halt any histamines released by them.

Dr Ben Lynch, and Dr Bill Walsh, both leading methylation experts, also support this hypothesis, as they believe that until the glutathione cycle is optimised, any methylation interventions will be unsuccessful.

In summary, the CYP450 medication, inflammation, and histamine connection is proven. Glutathione provides a proven protective measure when taking CYP450 medication.

Personally, my mast-cell activation symptoms have been greatly helped by increasing my glutathione levels. When I started this journey I could not tolerate quercetin, vitamin c, and a very broad range of foods. Raising my glutathione levels has gradually allowed me to tolerate a broader range of foods, my body is less sensitive to a broad range of environmental triggers, and my mast-cell activation disorder is effectively in remission.

Pier Francesco Mannaioni, Emanuela Masini, “The Release of Histamine by Free Radicals,” Free Radical Biology and Medicine, Volume 5, Issue 3, 1988, Pages 177–197

Enjoyed This Post?
Sign up for Monthly Updates. Its FREE!
Print This Post Print This Post

  • Pingback: The Histamine Intolerance IBS and IBD Connection - Alison Vickery()

  • Pingback: The Histamine Intolerance and Diamine Oxidase Connection - Alison Vickery()

  • Pingback: The Anti-depressant and Histamine Intolerance Connection - Alison Vickery()

  • chrissy

    I have just sent off for the dna base tests. I feel I have had histamine issues all my life. After a serious reaction to b12 injections in April I now suffer painful chronic hives daily, intestine and bladder pain. Last week a Uro/gyn guy has taken blood and urine to test for histamine, dao and other things as he feels the histamine is driven by an infection, possibly bladder or severe chemical allergies. You sound exactly as if you suffered similar reactions. How did you manage to overcome your mast cell disorder Alison. I don’t know where to begin. I have been low histamine diet now for over 6 months. My insomnia is super crazy. My histamine levels seem very high always around 3 am when the hives become really inflamed.

    • Hi Chrissy, if you can find the root cause, must progress can be made. Mine MACD was triggered by CYP450 mutations, which is phase 1 liver, but livelong DAO. It is important that there is a high incidence of liver issues (CYP450 or Methylation) with MACD. I did not sleep for 2 years so I can so relate to insomnia as an issue

      • chrissy

        I am severely depressed and anxious now because of insomnia Alison. I even have strong sleeping tablets that do nothing. How on earth did you manage. I feel I am at the end of my tether and constantly feel suicidal now. How can one Carry on with just an hours sleep in 24. It is slowly killing me and has been going on now fir almost 4 months. I am so so desperate.

        • Hi Chrissy I am sorry to hear of how desperate you have become. You need to go and see a functional doctor and ask for him to help you. There is an answer. I would also suggest that if medication is not working as you intended then it would be important to be tested for drug tolerance.

          • chrissy

            I have just posted back the DNA dose test, but living in the UK it will take some time to reach the lab and then get my results.

          • Awesome! Hope it yields you answers. I think everyone should have this test!

          • Awesome.

  • chrissy

    Hi Alison,
    My dao is 6.8. The histamine blood and urine came out fairly high, pointing towards a histamine intolerance. Would the dnabase tests show up anything that would help establish any problem?

  • Pingback: Drug Tolerance Testing and Why You Should Not Use Online Report Readers - Alison Vickery()

  • Colette

    Hi Alison,

    I am currently being tested for mast cell disease due to allergy sensitivities. My 11 Beta-Prostaglandin F2a/24h came back high. Also, my DAO A24464G and DAO G8864A show mutation.

    My two questions are…

    1) My doctor said I should avoid glutathion at all cost (I never understood why…). Isn’t this found in bone broth? I made bone broth before I saw my doctor and had it for a few days and noticed a big difference with my sensitivities and not as reactive to allergens. I want to try glutathion itself, but now concerned to given my doctors instructions to avoid.

    2) I used to be able to tolerate ZzzQuil (similar to NyQuil). I never used to react to it, but the last time I did, I slept 11 hours and learned the following morning that I had slept through a fire at my apartment complex! Scary! (I only had a itty bitty sip, not even near the recommended dose.) On the same note, on a separate day — I had dried fruit (organic, and no sulfites)… I ended up waking up in the middle of the night, drunk. I don’t even drink alcohol. Now, I act/feel drunk with dried fruit. Any ideas as to why this might be? No doctor has been able to help me figure out what is going on. I’ve been questioning my liver because of discolored urine and stools (also new symptoms).

    Thank you very much for your articles. They have been so helpful.

    • Hi Collette sounds like you have a lot going on and that you might be getting some answers. I cannot give personal advice on the blog as I need a full history and that would require you to be a client. You should not take something that your doctor says would not be right for you and I would encourage you to challenge them and ask them for the reasons. Once you have an accurate diagnosis then the answers will be clear. I hope you get an answer soon.

  • Pingback: The Bio-Individual Triggers of Histamine Intolerance()

  • Patricia

    Hi Alison, I also developed MCAS due to medication and gene mutations on cyp3a4.
    I have a question that I hope you could help me with…
    My thought is to lower all medications to help my body heal from oxidative stress, I only take daily desloratadine. The problem is that I get so many symptoms with a lower dose antihistaminer… Even though I eat low histamine food, low inflammatory, organic, glutenfree, low sal and also extra natural antihistamines like nigella sativa and quercetin.
    I just feel so much better with more desloratadine in my body… But I think it affects me badly in the long run (in perspective of oxidative stress).
    Do you have and thoughts?
    My goal is to feel better and I could manage to get more symptoms on the road of healing if that is (no meds) the right way to go?

    • Given the nature of your question to receive personal attention from Alison, specific to your individual needs, it would be best to book a comprehensive health review here Alison cannot give personal advice as you are not her client.