Statins may interact to damage the mitochondria

[CopiusAlf]

Statins may interact to damage the mitochondria

MAGGIE FOX

Reuters

February 24, 2008 at 8:29 PM EST

Full Story (http://www.theglobeandmail.com/servlet/story/RTGAM.20080224.wstatins0224/BNStory/specialScienceandHealth/home)

WASHINGTON — A new panel of tests aimed at finding out how drugs may damage cells has turned up a series of interactions that may explain some of the serious side-effects of statin drugs, researchers said on Sunday.

WASHINGTON — A new panel of tests aimed at finding out how drugs may damage cells has turned up a series of interactions that may explain some of the serious side-effects of statin drugs, researchers said on Sunday.

Statins, the wildly popular cholesterol-lowering drugs, may interact with at least one blood pressure drug to damage the mitochondria, the powerhouses of cells, the researchers reported in the journal Nature Biotechnology.

Their study also may lead to the development of drugs to treat diabetes and diseases of aging and better ways to screen for drug side-effects, the researchers said.

Vamsi Mootha of the Broad Institute at Harvard University and the Massachusetts Institute of Technology said they had made their new database freely available to other scientists to use for screening drugs.

The mitochondria are structures in cells that make adenosine triphosphate, or ATP, which helps power cells. Dr. Mootha's team tested more than 2,000 drugs on cells to see how they might interfere with this process.

Their test looks at gene function, ATP levels and other measures of how well the mitochondria are working.

Many patients who take statins have reported side-effects that include muscle pain and weakness. The cause is not well understood but Dr. Mootha has long suspected the mitochondria are involved. The effects have been hard to pin down because studies of different groups have produced conflicting results.

Dr. Mootha's team said their findings showed some statins lower ATP levels and interfere with the mitochondria.

"Of the six statins present in our screening collection, three (fluvastatin, lovastatin and simvastatin) produced strong decreases in cellular ATP levels and (mitochondrial) activity," they wrote.

Fluvastatin is sold by Novartis under the brand name Lescol, lovastatin is sold under the brand name Mevacor and simvaststin is sold as Zocor.

Three others -- atorvastatin, made by Pfizer under the brand name Lipitor, pravastatin or Pravachol, made by Bristol Myers Squibb and rosuvastatin, sold under the Crestor brand name by AstraZeneca -- had little effect, they said.

"We asked what pattern of dysfunction they cause in the mitochondria," Dr. Mootha said in a telephone interview. "Once we figured out what the pattern was we asked what other FDA-approved drugs give rise to that same pattern of mitochondrial dysfunction."

They found a few.

"We were struck by the fact that one of these nearest-neighbour drugs is propranolol, a widely used antihypertensive agent," they wrote.

Propranolol is a so-called beta blocker drug sold by Wyeth under the brand name Inderal and also available generically.

"That was a bit of a surprise," Dr. Mootha said. "And it is important because so many patients are on a statin as well as blood pressure medication."

Other drugs that resembled statins in their activity in mitochondria included amoxapine, cyclobenzaprine, griseofulvin, pentamidine, paclitaxel, propafenone, ethaverine, trimeprazine and amitriptyline.

A similar process may be going on in diabetes, nerve degeneration and aging, Dr. Mootha's team said. They found a number of drugs, including the cancer drug vinblastine may counter this process.

Dr. Mootha cautioned that his group has worked only in batches of muscle cells grown in the lab so far and that far more tests are needed.

[MizKitty]

Don't need "far more tests" to prove it to me. It happened to me. Statins all but dissolved my muscles. I was simultaneously on blood pressure meds, too.

[joedoro]

Now this is really useful information.

No citation given as to where to find the study.

Not based on any clinical data "Dr. Mootha cautioned that his group has worked only in batches of muscle cells grown in the lab so far and that far more tests are needed."

Impossible to know whether this has anything to do with the side effects that are seen with statins. It has yet to be determined that the cause of statin side effect are due to mitochrondrial dysfunction in the first place. Please remember, EVERY drug has side effects, even lowly vitamin C in patients as risk of lung cancer. The decision to be made whenever one uses a medication is whether the benefits outweigh the risks. Just becasue a medication has a side effect does not in itself make it bad.

Unfortunatley, this is just another example of a typical scientific illiterate press reporting to a scientific illiterate population.

[LessLiz]

Citation (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html)

I am not certain what it means that this is listed in the journal as a "resource" rather than an article or a communication, both terms I understand. It's dangerous to make conclusions about scientific inquiry from an abstract or a media report.
*******
Resources abstract

Nature Biotechnology
Published online: 24 February 2008 | doi:10.1038/nbt1387

Large-scale chemical dissection of mitochondrial function

Bridget K Wagner1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1),5 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a5), Toshimori Kitami1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1),2 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a2),5 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a5), Tamara J Gilbert1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1), David Peck1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1), Arvind Ramanathan1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1), Stuart L Schreiber1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1), Todd R Golub1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1),3 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a3) & Vamsi K Mootha1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1),2 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a2),4 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a4)

Abstract

Mitochondrial oxidative phosphorylation (OXPHOS) is under the control of both mitochondrial (mtDNA) and nuclear genomes and is central to energy homeostasis. To investigate how its function and regulation are integrated within cells, we systematically combined four cell-based assays of OXPHOS physiology with multiplexed measurements of nuclear and mtDNA gene expression across 2,490 small-molecule perturbations in cultured muscle. Mining the resulting compendium revealed, first, that protein synthesis inhibitors can decouple coordination of nuclear and mtDNA transcription; second, that a subset of HMG-CoA reductase inhibitors, combined with propranolol, can cause mitochondrial toxicity, yielding potential clues about the etiology of statin myopathy; and, third, that structurally diverse microtubule inhibitors stimulate OXPHOS transcription while suppressing reactive oxygen species, via a transcriptional mechanism involving PGC-1http://www.nature.com/__chars/alpha/black/med/base/glyph.gif and ERRhttp://www.nature.com/__chars/alpha/black/med/base/glyph.gif, and thus may be useful in treating age-associated degenerative disorders. Our screening compendium can be used as a discovery tool both for understanding mitochondrial biology and toxicity and for identifying novel therapeutics.



(http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#top)
Broad Institute of Massachusetts Institute of Technology and Harvard, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02446, USA.
These authors contributed equally to this work.
Correspondence to: Vamsi K Mootha1 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a1),2 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a2),4 (http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1387.html#a4) e-mail: vamsi~hms.harvard.edu

[joedoro]

Thanks for the citation.

Interesting, Mootha, who is probably the famous one is the 7th author listed but is the one who did the phone interview.

While I have no doubt that this is interesting research and may have some impact someday, for a newspaper to report and imply that this might have anything to do with humans at this point is just plain ludicrous.

No wonder people are so confused as to what to do when it comes to health.

[MizKitty]

Frankly, I'm surprised anything anti-statin sneaked through. Big Pharma's biggest cash cow. Hitmen are probably being dispatched as we type...

[tom sawyer]

Joedoro we already know that some of the more severe side effects of statins occur in muscle tissues which contain plenty of mitochondria due to the high requirement for ATP. I think this is a plausible explanation of what could be going on. If we were in the beginning stages of drug development and no human data existed, then I would agree with you.

Taken with the recent study about how mitochondrial malfunction causes serious problems for a cell, it does make a nice story and a place for jumping into more definitive studies.

On the other hand, the effects on mitochondria could just be part of a cascade effect that starts elsewhere in the cell and affects many if not all of the cellular components.

[eryalen]

Frankly, I'm surprised anything anti-statin sneaked through. Big Pharma's biggest cash cow. Hitmen are probably being dispatched as we type...
The statins are going off patent. They're developing new drugs that will be even more profitable.

[KarenJ]

Frankly, I'm surprised anything anti-statin sneaked through. Big Pharma's biggest cash cow. Hitmen are probably being dispatched as we type...


"So Devlin-McGreggor could give you....... Provasic!"

(-Harrison Ford as DOCTOR Richard Kimball, The Fugitive (http://en.wikipedia.org/wiki/The_Fugitive_(1993_film)) )

:lol: OK, so I had a little wine. I just love that movie.

[joedoro]

Joedoro we already know that some of the more severe side effects of statins occur in muscle tissues which contain plenty of mitochondria due to the high requirement for ATP. I think this is a plausible explanation of what could be going on. If we were in the beginning stages of drug development and no human data existed, then I would agree with you.

Taken with the recent study about how mitochondrial malfunction causes serious problems for a cell, it does make a nice story and a place for jumping into more definitive studies.

On the other hand, the effects on mitochondria could just be part of a cascade effect that starts elsewhere in the cell and affects many if not all of the cellular components.

Three others -- atorvastatin, made by Pfizer under the brand name Lipitor, pravastatin or Pravachol, made by Bristol Myers Squibb and rosuvastatin, sold under the Crestor brand name by AstraZeneca -- had little effect, they said.

So the biggest selling statin in the world which was responsible for the most complaints that I heard from in patients taking statins, probably because that was the one most of them were on, had little effect as quoted above. Since I couldn't be bothered to read the article I shouldn't comment, but it seems to me that there are alot of people complaining of muscle problems that are on one of the statins that didin't cause mitochondrial damage. Maybe I'm way off base but maybe the mitchondrial problems don't cause the side effects?

[joedoro]

"So Devlin-McGreggor could give you....... Provasic!"

(-Harrison Ford as DOCTOR Richard Kimball, The Fugitive (http://en.wikipedia.org/wiki/The_Fugitive_(1993_film)) )

:lol: OK, so I had a little wine. I just love that movie.

But I forget how the one armed guy who killed his wife fit in, in the movie.

All I know is if I had an MI I'd sure as hell would take a statin - who knows how they do it , doubt it's lowering LDL, but in patients with heart disease they sure do work.

Now as for the promotional bull with Jarvik -36 % risk reduction in people with risk factors for heart disease, relative risk, that is - that's ludicrous. (Take Liptior and decrease your chances of having an event from 3/100 -placebo group- to 2/100 in the Lipitor group) And keep the Pfizer machine grinding along.

[Nancy LC]

All I know is if I had an MI I'd sure as hell would take a statin - who knows how they do it , doubt it's lowering LDL, but in patients with heart disease they sure do work.
With a NNT of 250... I guess if you're the 1 out of 250 they work for then sure!

http://www.businessweek.com/magazine/content/08_04/b4068052092994_page_2.htm

[KarenJ]

But I forget how the one armed guy who killed his wife fit in, in the movie.

All I know is if I had an MI I'd sure as hell would take a statin - who knows how they do it , doubt it's lowering LDL, but in patients with heart disease they sure do work.

Now as for the promotional bull with Jarvik -36 % risk reduction in people with risk factors for heart disease, relative risk, that is - that's ludicrous. (Take Liptior and decrease your chances of having an event from 3/100 -placebo group- to 2/100 in the Lipitor group) And keep the Pfizer machine grinding along.

The one-armed man was head of security at the drug company. Dr. Kimball seems to think he had something to do with his wife's murder.

I highly recommend that movie.

I don't think drug companies should be allowed to use relative risk numbers in their advertising. It's extremely misleading, they know it, and they promote it. The Pharma companies tricking adults in just the same way that Fast Food companies are tricking kids. Slick.

So, since statins lower cholesterol by interfering at that rate limiting step (also limiting the making of CoQ10), and they are also doing something detrimental in the mitochondria, might they be interrupting something critical in the oxidative phosphorylation pathway? There are so many reactions that go on there, it's mind boggling.

[joedoro]

With a NNT of 250... I guess if you're the 1 out of 250 they work for then sure!

http://www.businessweek.com/magazine/content/08_04/b4068052092994_page_2.htm


That number refers to the use of statins in primary prevention which is different from secondary prevention, that is using statins in people who have risk factors for heart disease but who do not have it in order to prevent the first clinical event vs using them in those that have already have had a cardiac event in order to prevent subsequent events. These are very different types of people.



Here's a link to the meta analysis done looking at primary and seconday outcome studies http://64.233.167.104/custom?q=cache:wxj3L2jI88cJ:www.dustri.com/ze/cp/samplecopy/cp12567.pdf+NNT+statins+symptomatic+heart+disease&hl=en&ct=clnk&cd=7&gl=us&client=pub-5386907765195439

Conclusions:
This overview indicates that statin treatment
reduces the relative risk of occurrence of cor-
onary events, cardiovascular disease mortal-
ity, non-fatal strokes and all-cause mortality.
While secondary prevention with statins pro-
vides considerable improvement of cardio-
vascular morbidity/mortality, primary pre-
vention with statins provides only small and
clinically hardly relevant improvement of
cardiovascular morbidity/mortality.

[joedoro]

The one-armed man was head of security at the drug company. Dr. Kimball seems to think he had something to do with his wife's murder.

I highly recommend that movie.

I don't think drug companies should be allowed to use relative risk numbers in their advertising. It's extremely misleading, they know it, and they promote it. The Pharma companies tricking adults in just the same way that Fast Food companies are tricking kids. Slick.

So, since statins lower cholesterol by interfering at that rate limiting step (also limiting the making of CoQ10), and they are also doing something detrimental in the mitochondria, might they be interrupting something critical in the oxidative phosphorylation pathway? There are so many reactions that go on there, it's mind boggling.

That's right - he was the security guard. Even not being a fan of big Pharma, I thought it was just bit too much in portray8ing them as they did.

As for how the statins work or cause side effects, who knows? But now that we have this mitochondrial paper out, according to the public, it's a done deal.