Key takeaways:
- The ABCC4 (MRP4) gene encodes an efflux transporter that moves certain medications, toxins, and natural signaling molecules out of cells.
- ABCC4 genetic variants can alter transporter activity, which is associated with altered levels and side effects for certain medications, including chemotherapy drugs.
- Environmental toxins, medications, inflammation, and natural supplements can all interact with ABCC4 and potentially change how it transports drugs out of cells.
What does ABCC4 (MRP4) do?
ABCC4 is an efflux transporter that moves certain compounds out of a cell. The ABCC4 transporter was originally called the multi-drug resistance protein 4 (MRP4) because it actively pumps compounds, including many medications, out of a cell, which is called cellular efflux.
ABCC4 is found in many tissues throughout the body, but it is particularly important in the kidneys, blood-brain barrier, liver, and platelets. It moves substances made in the body (endogenous substances), including prostaglandins, cAMP, urate, and certain estrogen metabolites, out of the cell. It is also an essential way that cells can get rid of toxins and medications.
ABCC4: Drug and toxin efflux from cells
A lot of genetic research focuses on common variants in ABCC4 that affect how well specific medications work and whether you are likely to get side effects.
Drugs that are moved out of cells by ABCC4:[ref] [ref][ref][ref][ref][ref]
- Antiviral nucleoside/nucleotide analogs: tenofovir, ganciclovir, valganciclovir, PMEA, and adefovir.
- Anticancer/cytostatic drugs: methotrexate, leucovorin, thiopurine metabolites, 6-mercaptopurine, 6-thioguanine, cytarabine, and topotecan-related or nucleotide-based chemotherapies.
- Antibiotics: fluoroquinolones like ciprofloxacin.
- Cardiovascular and diuretic agents: furosemide, hydrochlorothiazide
Natural supplements moved out of cells by ABCC4:[ref]
- Ginsenoside compound K from ginseng
- quercetin
Drugs and supplements that can inhibit ABCC4:[ref][ref][ref][ref]
- NSAIDs (ibuprofen, diclofenac, celecoxib, naproxen)
- sildenafil
- montelukast
- dipyridamole
- losartan
- salicylate
Environmental toxins:
Genetic variants that increase or decrease the expression of ABCC4 are fairly common and can affect the response to medications, how a natural supplement works, or how well you detoxify certain substances. For example, variants in ABCC4 affect arsenic detoxification.[ref]
Endogenous substances: cAMP, cGMP and ABCC4
cAMP and cGMP are what are called second messengers – signaling molecules that are involved in sending the signal inside the cell when something activates a cell membrane receptor. cAMP activates protein kinase A in cells to regulate metabolism, synaptic transmission, and adrenaline response. cGMP activates protein kinase G and ion channels, helping relax muscles or control vision.[ref] These two second messengers act in many different cell types and, well, trigger a bunch of different cellular actions.
ABCC4 moves cAMP and cGMP out of cells as a way to regulate the intracellular concentration. Essentially, ABCC4 helps to modulate the signaling inside of a cell by moving any excess cAMP or cGMP out of the cell.[ref]
ABCC4 and platelet aggregation:
Platelet aggregation is the process by which platelets clump together to form a blood clot. ABCC4 is found on the plasma membrane of platelets, where it acts to export cyclic nucleotides like cAMP. By pumping out cAMP, it prevents an excess of cAMP in the cell, which then modulates platelet activation and aggregation.[ref]
Another connection with ABCC4 is that the beneficial effects of aspirin therapy can be reduced in patients who overexpress ABCC4.[ref]
ABCC4 and prostaglandin E2:
Prostaglandins are lipid mediators that are synthesized from arachidonic acid and secreted by cells as a primarily pro-inflammatory signal. Prostaglandin E2 acts like a hormone that signals for inflammation, increased blood flow, fever, and swelling. It is also the signal released during childbirth to soften the cervix and start contractions.
Studies show that ABCC4 is the only efflux transporter for moving prostaglandin E2 out of cells, and it’s thus involved in regulating the levels of extracellular prostaglandin E2. Interestingly, NSAIDs can inhibit ABCC4, causing less prostaglandin E2 to be moved from cells into circulation. This may be one way that NSAIDs reduce inflammation.[ref][ref]
What regulates ABCC4?
The expression of ABCC4 on cell membranes can be influenced – increased or decreased – by other factors in the cell.
- Nrf2 activation: ABCC4 expression can be upregulated by activation of Nrf2 in response to polyphenols, toxins, or environmental pollutants. [ref]
- IL-13: Studies involving lymphoma patients show that IL-13 promotes the expression of ABCC4, which in turn causes resistance to some chemotherapy drugs in NK/T-cell lymphoma cells. [ref]
- IL-1B: Another study showed that in lung tissue, inflammation and increased IL-1B cause an increase in ABCC4 expression in the lungs. This could affect inhaled medication efficacy.[ref]
- MicroRNAs: MicroRNAs are short strands of RNA that block mRNA from being translated into its corresponding protein. This is one way that gene expression is controlled in cells. microRNA-124a and microRNA-506 decrease ABCC4 protein expression by up to 50%.
- TNF-alpha: In a study involving patients with obstructive cholestasis (blocked liver bile), the researchers found elevated ABCC4 levels. Further experiments showed that TNF-alpha, an inflammatory cytokine, causes ABCC4 expression to increase.[ref]
- Sp1 transcription factor: The ubiquitous transcription factor Sp1 is responsible for the baseline expression of ABCC4. Sp1 is kind of a general regulator, but it can be upregulated (and thus increase ABCC4) in cancer or inflammation.[ref]
To sum up here: ABCC4 levels aren’t static and can be affected by inflammation or Nrf2 activation. Thus, the levels of ABCC4 dynamically change in times of inflammation or due to interactions with toxins and drugs. This is in addition to inherited changes in how your ABCC4 gene works at a base level.
Let’s switch gears and take a look at your genotypes for ABCC4 variants:
Genotype report: ABCC4
The following variants have been shown in studies to have an effect on medication levels or side effects. Keep in mind that these variants could interact with environmental factors, other drugs, or other genetic variants. So it isn’t as straightforward as being able to say that a single SNP will cause the same effect on a medication for everyone. Instead, take this as a ‘heads up’ to talk with your doctor about the possible effects on medications.
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Lifehacks: Modulating ABCC4
Note that drug metabolism and the response to medications are complex topics that depend on more than just a single gene or single SNP. In addition, some of the studies on ABCC4 and medications are dependent on the concentration of the drug.[ref]
Talk with your doctor and pharmacist for help with prescription medications. The list of inhibitors and inducers below will give you a starting point for asking questions.
Common inhibitors of ABCC4:
Keep in mind that inhibiting ABCC4 can increase the levels of medications within the cell, possibly leading to increased side effects.
- NSAIDs – non-steroidal pain medications such as indomethacin, sulindac, ibuprofen, or naproxen – can inhibit ABCC4. [ref]
- Quercetin is a moderate inhibitor of ABCC4 (as well as a couple of other drug efflux transporters).[ref]
- Silymarin (milk thistle) inhibits ABCC4 and other drug efflux transporters.[ref]
- Hesperidin inhibits ABCC4 and other drug efflux transporters.[ref]
Increasing ABCC4 efflux:
- Sulforaphane is an Nrf2 activator that increases the expression of ABCC4.[ref]
- Glycyrrhetinic Acid (licorice) increases MRP4 expression in the liver (animal study), likely due to Nrf2 activation.[ref]
- Panex ginseng increases MRP4 expression, again likely due to Nrf2 activation (animal study).[ref]
- Forskolin acts as a direct activator of adenylyl cyclase, raising intracellular cyclic AMP (cAMP) levels, which in turn promotes ABCC4 (MRP4)-mediated cellular efflux of cAMP and signaling regulation. [ref]
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Related articles and topics:
ABCB1 (P-glycoprotein): Response to Medications, HRT, and Environmental Toxins
Nrf2 Pathway: Increasing the Body’s Ability to Get Rid of Toxins
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