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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 25, 2014

A New Way to Study Hepatotoxicity

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Posted by Derek

Every medicinal chemist fears and respects the liver. That's where our drugs go to die, or at least to be severely tested by that organ's array of powerful metabolizing enzymes. Getting a read on a drug candidate's hepatic stability is a crucial part of drug development, but there's an ever bigger prize out there: predicting outright liver toxicity. That, when it happens, is very bad news indeed, and can torpedo a clinical compound that seemed to be doing just fine - up until then.

Unfortunately, getting a handle on liver tox has been difficult, even with such strong motivation. It's a tough problem. And given that most drugs are not hepatotoxic, most of the time, any new assay that overpredicts liver tox might be even worse than no assay at all. There's a paper in the latest Nature Biotechnology, though, that looks promising.

What the authors (from Stanford and Toronto) are doing is trying to step back to the early mechanism of liver damage. One hypothesis has been that the production of reactive oxygen species (ROS) inside hepatic cells is the initial signal of trouble. ROS are known to damage biomolecules, of course. But more subtly, they're also known to be involved in a number of pathways used to sense that cellular damage (and in that capacity, seem to be key players in inducing the beneficial effects of exercise, among other things). Aerobic cells have had to deal with the downsides of oxygen for so long that they've learned to make the most of it.
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This work (building on some previous studies from the same group) uses polymeric nanoparticles. They're semiconductors, and hooked up to be part of a fluorescence or chemiluminescence readout. (They use FRET for peroxynitrite and hypochlorite detection, more indicative of mitochondrial toxicity, and CRET for hydrogen peroxide, more indicative of Phase I metabolic toxicity). The particles are galactosylated to send them towards the liver cells in vivo, confirmed by necropsy and by confocal imaging. The assay system seemed to work well by itself, and in mouse serum, so they dosed it into mice and looked for what happened when the animals were given toxic doses of either acetominophen or isoniazid (both well-known hepatotox compounds at high levels). And it seems to work pretty well - they could image both the fluorescence and the chemiluminescence across a time course, and the dose/responses make sense. It looks like they're picking up nanomolar to micromolar levels of reactive species. They could also show the expected rescue of the acetominophen toxicity with some known agents (like GSH), but could also see differences between them, both in the magnitude of the effects and their time courses as well.

The chemiluminescent detection has been done before, as has the FRET one, but this one seems to be more convenient to dose, and having both ROS detection systems going at once is nice, too. One hopes that this sort of thing really can provide a way to get a solid in vivo read on hepatotoxicity, because we sure need one. Toxicologists tend to be a conservative bunch, with good reason, so don't look for this to revolutionize the field by the end of the year or anything. But there's a lot of promise here.

There are some things to look out for, though. For one, since these are necessarily being done in rodents, there will be differences in metabolism that will have to be taken into account, and some of those can be rather large. Not everything that injures a mouse liver will do so in humans, and vice versa. It's also worth remembering that hepatotoxicity is also a major problem with marketed drugs. That's going to be a much tougher problem to deal with, because some of these cases are due to overdose, some to drug-drug interactions, some to drug-alcohol interactions, and some to factors that no one's been able to pin down. One hopes, though, that if more drugs come through that show a clean liver profile that these problems might ameliorate a bit.

Comments (13) + TrackBacks (0) | Category: Drug Assays | Drug Development | Pharmacokinetics | Toxicology


COMMENTS

1. Tony on March 25, 2014 11:29 AM writes...

They really should run some tests on Keith Richards to find out what he's got going on.

An immunologist friend of mine speculated that when cloned organs become available the Keith Richards model will be like an old-school Midas muffler -- guaranteed for life. Possibly you'll even be able to buy one and hand it down to your grandchildren.

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2. NJBiologist on March 25, 2014 11:41 AM writes...

As a technology, this is fascinating. But as an assay, I'm not sure I see an advantage over the usual Hy's Law test (transferase + bilirubin measurements). In fact, this would seem to have the potential to pick up false positives--compounds that increase ROS, but fail to kill hepatocytes. It seems like a predictor of the Hy's Law cases, which are in turn a predictor of hepatotoxic agents.

@1 Tony--And if the Keith Richards model is sold out, you could look for the John Lydon model....

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3. Morten G on March 25, 2014 12:00 PM writes...

Does it have to be in mice?

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4. Derek Lowe on March 25, 2014 12:21 PM writes...

#3 Morten -

That occurred to me as well. You'd have to prove safety in humans, of course, but that would really be the ultimate liver test, wouldn't it?

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5. redfiona99 on March 25, 2014 12:22 PM writes...

Not related to the post but related to point 1 - not Keith Richards but I know that Ozzy Osbourne has had his DNA sequenced to see why he isn't dead yet.

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6. anon the II on March 25, 2014 3:58 PM writes...

@ 3&4

My guess is that the light from the FRET or CRET wouldn't make it's way out of a thicker animal. Just a guess.

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7. Anonymous on March 25, 2014 5:05 PM writes...

Dear Derek,
Your friendly toxicologists do not need additional fancy technics to identify drug-induced liver damage in rats. We can simply kill the poor critter, cut a piece of liver out and feed it to a pathologist. That has so far proven to be the most reliable way to identify hepatic injury, regardless of the mechanism of toxicity. The problem is that our friendly rodents are frequently a poor substitute for humans (Olson, Betton et al., 2000) so if this method is usable in patients and one can show that it correlates well with tissue injury, then we might have a better method to identify severe cases of DILI that an autopsy and I am confident my colleagues will be interested... If it is just another expensive way of detecting Tylenol hepatic effects in rodents, you will have to excuse me while I yawn...
From SOT in Phoenix with love!

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8. A Brit on March 26, 2014 2:50 AM writes...

While acknowledging the modest sample size (n=3) and the observational nature of the data, I should point out that the impressive livers mentioned above (Keith Richards, Ozzy Osborne, John Lydon/Jonny Rotten) all originated in the UK. I wonder if this means that the UK is the place to do your expensive phase III trials, if you don't want awkward liver toxicity signals messing things up?

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9. Anonymous on March 26, 2014 7:18 AM writes...

It's acetAminophen...

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10. Another Brit on March 26, 2014 9:45 AM writes...

@9 it's paracetamol

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11. Lisa Basset on March 28, 2014 12:07 PM writes...

and hooked up to be part of a fluorescence or chemiluminescence readout. (They use FRET for peroxynitrite and hypochlorite detection, more indicative of

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12. Raj on April 1, 2014 8:17 PM writes...

Nice job with the simultaneous detection. However, the ROS part in both Rao (this paper) and earlier Murthy fail to mention that the chemistry and assays have been been done in the invitro world and commercialised as LOCI (Siemens) and ALPHA (PKI) - and yours truly presented the invivo version with mice data at last years WMIC meeting in Savannah Ga. The chemistry group at Syva/Syntex did a fabulous job but alas all of it lies buried in patents...

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13. Virgil on April 14, 2014 10:53 AM writes...

Just posted over at PubPeer. The data would appear to have some problems.
http://pubpeer.com/publications/24658645

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