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Giving the liver a new way to deal with paracetamol overdose

A study published today in Stem Cells Translational Medicine shows that microRNAs could be used to treat paracetamol overdose. Lead researcher Dr David Hay from the MRC Centre for Regenerative Medicine at the University of Edinburgh spoke to Sylvie Kruiniger about his findings, made possible by growing and testing their own stem cell-derived liver cells.

Dr David HayWhy is it important to study paracetamol overdose?

Taken at recommended levels, paracetamol is usually safe, effective and is used widely in adults and children, either alone or in combination with other drugs.

However, it can damage the liver and the risk of liver damage increases with doses over the recommended levels. Each year we see around 200 deaths involving paracetamol (National Office for Statistics).

What happens in your liver when you take paracetamol?

When the liver processes a recommended dose of paracetamol, most of the drug is broken down by acid into water-soluble forms that can be passed in the urine or exported to the bile: this is called the sulfation pathway.

Around five per cent is turned into a toxin called N Acetyl-p-Benzo Quinone Imine (NAPQI). At this low level, the liver can clear the toxin with an antioxidant that reacts with NAPQI so it can be excreted in urine and bile.

So what happens if you take too much?

If we take too much paracetamol, the liver cannot process enough of the paracetamol using the sulfation pathway and so more of the NAPQI toxin is produced.

When the liver cells try to cope with the toxin by deploying the antioxidants, its store is quickly depleted. As a result, liver cells die and the liver becomes inflamed which, untreated, can lead to organ failure and death.

How might your findings change how we treat overdose in the future?

Our work focused on the major cell-type found in the liver, the hepatocyte. This cell makes up 70-80 per cent of the liver and is the main site of damage in paracetamol poisoning.

Current clinical practice for treating paracetamol overdose is to substitute the antioxidant by giving a compound which is highly efficient at neutralising the NAPQI toxin. However, this compound can cause allergic reactions and nausea in patients.

Instead of replacing or boosting the antioxidant levels, we wanted to find a way for the liver to process more of the paracetamol safely. We aimed to do this by increasing the levels of proteins involved in the sulfation pathway.

How does it work?

We found that by introducing a microRNA inhibitor, antagomir 324, we could increase the number of proteins used in the sulfation pathway and this meant that the number of cells dying decreased.

MicroRNAs are small non-coding RNAs – cellular components that fine tune ‘gene expression’ which determines how many proteins are produced. Non-coding RNAs have already been used safely in pre-clinical studies to treat atherosclerosis and virus replication in mice and primates; phase I clinical trials using them are underway to treat cancer.

We also exposed the liver cells to plasma from patients with liver failure caused by an overdose of paracetamol and found that antagomir 324 supported the cells.

Where did you get your liver cells from?

The liver ‘model’ used in our studies was generated from stem cells. First, we established that our stem cell-derived liver cells made the correct genes to process paracetamol, then we performed large-scale characterisation of the stem cell-based liver model.

The benefit of our system is that we can produce a limitless number of liver cells that can be compared between different experiments. This is something that cannot be done with cells derived from donor organs, as the banks of those cells eventually run out.

What implications might this have for animal research?

Generating liver cells from stem cells allows us to recreate human physiology ‘in a dish’. These liver models have been validated in collaboration with the pharmaceutical industry and will ultimately lead to a reduction in the use of animals in academic research and industrial drug development, though animal models are likely to remain important for pre-clinical research.

What are the next steps for your research?

One key question for developing any targeted therapy is how to deliver the microRNA to a specific cell, in our case to liver cells. As we move to the pre-clinical stage, we will explore the use of liposomes and nanomaterials which are available at clinical grade deliver antagomir 324 in a rodent model.

Our future work will also study antagomir 324’s protective nature and any side effects that may arise. MicroRNAs can target multiple parts of the cell and this might mean that it damages cells or reduces its effectiveness as a therapy. If these preclinical assessments are successful, we will be in a position to take these studies toward clinical trials.

Is there potential for developing other treatments using your liver model?

I think our stem cell-derived system has an important role to play in modern medicine. We have successfully used stem cell-derived liver cell models to study how humans process drugs, liver injury caused by drugs and virus infection and replication.

The ability to model human health and disease ‘in a dish’, from a renewable resource, has allowed us to move away from surrogate liver models, for example liver cancer cell lines, which can have chromosome abnormalities.

We believe that this is an important shift that will lead to the identification of new medicines and the repositioning of existing drugs to treat human liver disease.

Paper: Reducing Hepatocyte Injury and Necrosis in Response to Paracetamol Using Noncoding RNAs

 

3 Comments Post a comment
  1. Steve Hawkins #

    Some years ago there was quite a lot of media coverage of a campaign to make paracetamol be sold in combination with methionine, which was said to make it much less damaging to the liver. I believe there is actually one brand that makes the combine drug, but, since that initial publicity, I’ve never seen anything in the medical media encouraging the use of this simple method of protecting people from overdose damage. Though this new work is clever and may save a few of those 200 deaths, it seems typical of our health system that we would rather spend a fortune on trying to repair needless damage than take simple measures that would prevent it happening in the first place.

    April 11, 2016
    • Sylvie Kruiniger #

      Hi Steve,

      Thanks for getting in touch. The BMJ published a discussion on the pros and cons of methionine which you may find interesting http://www.bmj.com/content/315/7103/301

      Best wishes,

      Sylvie
      MRC Science Writer

      April 14, 2016
      • Steve Hawkins #

        Hi Sylvie,

        Thanks for getting back to me and providing the extra links.

        I’m afraid I don’t have a BMJ subscription, so I can only read the intro to the resume, but what I can read does seem rather dismissive.

        I can, however, read the later article, by Keith Hawton, on the effect of the introduction of sales restriction in 1998. While Hawton did find there was a modest reduction in deaths from paracetamol in England and Wales, he still reports about 121 deaths per year and says more measures need to be taken. He also notes that the number of cases of admission for paracetamol poisoning itself has not declined, so the burden of overdose on the NHS is still high even if it does not now so often lead to the loss of the patient.

        http://www.bmj.com/content/346/bmj.f403?trendmd-shared=0

        Both the BMJ intro and the SmithKline reason for withdrawal, seem to hang on what appears to be a spurious point, that we do not know the effects of excessive amounts of methionine in the diet  (aren’t 121 deaths enough to make them want to find out?). This is surely unlikely to be a problem with the vast majority of people who just take them for the occasional headache or chill. I could say ‘that would hardly amount to a hill of beans’! 😉

        SmithKline is even callous enough to forget why the methionine was put in there in the first place, when it says that the ingredient is of no benefit to the majority of people! It seems they’ve had a change of heart since they formulated the drug, and now think people who overdose, for whatever reason, deserve to die!

        At least they say there is still another formulation available, but that is quite an old comment, because there is another comment that says UK restriction on pack size is not introduced yet.

        It seems to me that in a country where people routinely pump themselves full of vast numbers of nutritional supplements, there is little mileage in a complaint of forcing people to take a small amount of an amino acid when they have a headache, when it could save 121 lives per year, and many more hospitalisations for liver damage from overdose.

        I think that it is well worth looking again at this issue, and, perhaps you could take it up with Keith Hawton as a simple measure that would achieve his aims. 

        The only reason those people are still dying is because the government left it up to the drug cos as to whether they included methionine or not. SKB seems to have been the only one with a conscience about deaths caused by its product, until it saw that the other companies did not follow suit, and naturally withdrew it to save a small amount of money instead of human lives and NHS costs!

        The whole thing needs looking at again: Do a dosing study on methionine if really of any concern (can’t be worse than paracetamol!), but then get the MCA to insist that *all* manufacturers include methionine, and then Keith Hawton’s group can find something else to do.

        (Incidentally, my CoDydramol comes in boxes of 100)

        April 15, 2016

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