Tuesday, March 1, 2011

Oltipraz

Oltipraz is a drug that was originally used to treat intestinal worms. It was later found to prevent a broad variety of cancers (1). This was attributed to its ability to upregulate cellular detoxification and repair mechanisms.

Researchers eventually discovered that oltipraz acts by activating Nrf2, the same transcription factor activated by ionizing radiation and polyphenols (2, 3, 4). Nrf2 activation mounts a broad cellular protective response that appears to reduce the risk of multiple health problems.

A recent paper in Diabetologia illustrates this (5). Investigators put mice on a long-term refined high-fat diet, with or without oltipraz. These carefully crafted diets are very unhealthy indeed, and when fed to rodents they rapidly induce fat gain and something that looks similar to human metabolic syndrome (insulin resistance, abdominal adiposity, blood lipid disturbances). Adding oltipraz to the diet prevented the fat gain, insulin resistance and inflammatory changes that occurred in the refined high-fat diet group.

The difference in fasting insulin was remarkable. The mice taking oltipraz had 1/7 the fasting insulin of the refined high-fat diet comparison group, and 1/3 the fasting insulin of the low-fat comparison group! Yet their glucose tolerance was normal, indicating that they were not low on insulin due to pancreatic damage. The low-fat diet they used in this study was also refined, which is why the two control groups (high-fat and low-fat) didn't diverge more in body fatness and other parameters. If they had used a group fed unrefined rodent chow as the comparator, the differences between groups would have been larger.

This shows that in addition to preventing cancer, Nrf2 activation can attenuate the metabolic damage caused by an unhealthy diet in rodents. Oltipraz illustrates the power of the cellular hormesis response. We can exploit this pathway naturally using polyphenols and other chemicals found in whole plant foods.

44 comments:

Chris said...

Very interesting but any pointers as to which whole foods exactly would be best at mimicking the Oltipraz effect?

qualia said...

fascinating indeed! a comparison to, say, resveratrol would be intersting..

Paul said...

There is a word-for-word copy of your article at
http://googletrendnews.co.cc/oltipraz.php
I trust they are paying you well.

kathleen said...

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you have i really appreciate you work i will come back and read some more very soon

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www.healthandwellnessconsultants.com

Jenny said...

Every "high fat" diet I've seen in rodent studies has been a high carb/high fat diet. This is also true in human studies where the high fat diet usually includes fries and buns.

But given the major differences between rodent pancreata and human ones and their glucose metabolisms--NEVER cited by the researchers--one must never draw conclusions about human responses from these rodent studies.

It's also worth noting that the rodent models of abnormal blood sugar used in studies achieve their high blood sugars through mechanisms deriving from disturbing different genes than the ones found in any human with diabetes. This is never noted in the studies either.

That is why we have dozens of cures for rodent diabetes that don't transfer to humans.

Ross said...

Stephan,

Regarding the copy of your article that Paul spotted: this same thing happened several months ago at another blog I read. There is an extended discussion of how to deal with "site scrapers" here:

http://www.nakedcapitalism.com/2010/12/seeking-reader-help-with-evil-site-scrapers.html

Alex said...

It seems that Nrf2 is part of the body's response to smoking as well.

http://www.ncbi.nlm.nih.gov/pubmed/21030515

No wonder those Kitavans fared so well. Time to go light up.

Alex

Might-o'chondri-AL said...
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David said...

Is it currently being used to treat parasites? Is it available as a medicine currently? Or only as an experimental agent?

gunther gatherer said...

These hormesis posts are fascinating. Have you read about the Baltimore Shipyard Study on Seth Roberts' blog?

http://www.blog.sethroberts.net/2011/02/25/the-baltimore-shipyard-study/

a 25% lower death rate in those exposed to MORE radiation.

Might-o'chondri-AL said...
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Bill said...

"Nrf2 - Antioxidant Protein Also Promotes Clogging Of Arteries"

http://www.science20.com/news_articles/nrf2_antioxidant_protein_also_promotes_clogging_arteries

Stan (Heretic) said...

Re: ...the same transcription factor activated by ionizing radiation and polyphenols (2, 3, 4).

http://stan-heretic.blogspot.com/search/label/hormesis

john said...

Sulfuranes in broccoli activate NRF2pathways and are the reasons why this veggie has so many anti inflammatory and anti cancer effects. So its not all the dark fruits or chocolate that can do it!

Tom Bridgeland said...

I'm with Jenny on this one. If we fed grass to lions and observed poor outcomes, would we then go on to suggest that horses shouldn't eat grass? Who cares what rats eat, when we are talking about human diets?

Might-o'chondri-AL said...
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Adrián said...

"Predictably, drug companies are busy modifying oleanolic acid molecules to study and sell."

Indeed. Bardoxolone methyl seems to be a potent supressor of inflammation and a revolutionary treatment for CKD.

Lucas Tafur said...

Thank you for these series of posts, Stephan. Made me wonder about healthy smokers and smoking relationship with CVD. As Reaven has suggested, maybe smoking effects on CVD is due to aggraviating IR and MetS. With chronic inflammation and oxidative stress, cigrarette smoking causes more damage. But what about a healthy person?

Might-o'chondri-AL said...
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Austin said...

Thanks for the intersting post Stephan

@Chris: I know vinegar helps with insulin sensitivity...
http://care.diabetesjournals.org/content/27/1/281.long#ref-4

http://hfpn.blogspot.com/2011/02/nutraceuticals-vinegar.html

@ Might-o'chondri-AL, Do you know the mechanisms by which acetic acid helps regulate insulin?
Thanks I am just guessing non specific ADCY transcription because the effects seem to be acute?
Thanks

Might-o'chondri-AL said...
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Imgenex said...

Hello all,

Oltipraz is a schistosomicide. It is used in tumor prevention. Oltipraz may have the ability to affect blood vessel growth. Thanks a lot......

Nf-kb

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Might-o'chondri-AL said...
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dianaedd said...

I wish I understood what is meant by a "refined high fat diet"....Is the fat refined or something else?

Paleo 2.0 said...

Hi Dianne,

I believe "refined" is as in fats refined from plant seeds - corn oil, vegetable oil, etc...

Stephan said...

Hi Paul and Ross,

Thanks. There are several rip-off sites that use my material without attribution. It's annoying but I haven't had time to deal with it. Maybe I'll go after them at some point.

Hi Jenny,

The typical rodent high-fat diet (Research diets D12492 for example) is not high in carbs. It's 60% fat, 20% protein and 20% carbs. The carb comes from maltodextrin and sucrose.

Hi Gunther,

Yes, I read that. It's interesting although it seems like a difficult study to control properly.

Hi Bill,

I wouldn't extrapolate the effects of a genetic knockout to the effects of manipulating Nrf2 activity through diet or even pharmaceuticals. There are many examples of knockouts that have unexpected phenotypes. For example, knocking out IL-6 enhances atherosclerosis, but increasing it above baseline also increases atherosclerosis... If you only had the first data point, you'd guess that increasing IL-6 above baseline would protect against athero.

Stephan said...

Hi Tom and Jenny,

I wouldn't be so hasty to dismiss rodent studies, particularly rats. The more I learn about them, the more relevant I think they are to humans. They're omnivores that are adapted to eating starch, just like humans. All of their basic biochemistry works the same as us. Insulin, leptin, and gut peptides work in a similar manner. They have all the same central nervous system homeostatic and food reward machinery as we do.

They aren't just little humans, but I feel that rodent research is extremely useful for learning about many aspects of human health. Findings in rodents always need to be confirmed in humans, but in many cases they already have been.

Hi Lucas,

Heavy smoking is clearly harmful for anyone, healthy or not. The Kitavans and other non-industrial smokers only smoke 1-3 cigarettes a day. I think overall, smoking cigarettes is playing with fire as they are so clearly linked with so many diseases. It's possible that occasional smoking is no different than not smoking, or that it could even be hormetic. I don't know. But even if it were hormetic, I would never advise anyone to do it for their health because of the high risk for addiction.

Hi Diane and Paleo 2.0,

The diet is composed exclusively of refined ingredients: refined lard, soybean oil, isolated casein (milk protein), maltodextrin, sucrose (table sugar), cellulose (fiber) and vitamins and minerals.

Eric said...

Care to comment on the fact that the fat in D12492 is 90% lard and 10% soybean oil? This seems like a very unhealthy diet indeed. That much lard would contain far too much steroid hormone for these mice. And both of these fats are also very high in omega-6 without enough omega-3. In some other high-fat diet studies found (for instance, using coconut oil) no such adverse effects are found. Don't you think many of these high-fat studies in mice are at least a little flawed? At the very least, a (proper) high-fat diet in humans lowers insulin and inflammation, not raises it. So something in these studies is flawed.

Stephan said...

Hi Eric,

Yes, I'll comment on that. As far as I can tell, lard and soybean oil are the two best fats at making rodents obese. Researchers use this diet because it "works" very well-- it rapidly causes obesity and metabolic syndrome in rodents. Other fats, such as tallow, butter, coconut oil, and even some seed oils like safflower oil, don't seem to cause as much fat gain. However, almost any high-fat diet will predispose rodents to fat gain more than a low-fat diet, so it's just a matter of degree.

This diet (RD D12492) has also been shown to cause an extreme loss of serum long-chain omega-3 in rodents. Similar findings were recently reported in macaques. I think it's partially due to the n-6:3 imbalance of these diets, and partially due to other factors such as a total lack of polyphenols and other factors that can protect n-3s during digestion.

Regarding your statement "a (proper) high-fat diet in humans lowers insulin and inflammation, not raises it", I think that's true insofar as a high-fat, low-carb diet can cause fat loss in overweight people. But I doubt high-fat has any advantage in a lean healthy person.

Might-o'chondri-AL said...
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Austin said...
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Austin said...

@ Might-o'chondri-AL,
Thanks alot. That does help, at least I have a possible route to investigate now. I asked couple of the physio prof.s in my department had no idea what I was talking about. I was able to locate one study showing an interaction but did not mention which form ADCY.

Might-o'chondri-AL said...
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Austin said...

Hi Might-o'chondri-AL,

Thanks again. Interstingly enough, that search has led me to some promising research on caffeic acid.
Im reading full text now but according to the authors of one study, "caffeic acid may promote insulin receptor tyrosyl phosphorylation, up-regulate the expression of insulin signal associated proteins, including insulin receptor, phosphatidylinositol-3 kinase, glycogen synthase, and glucose transporter-2, increase the uptake of glucose, and alleviate insulin resistance in cells as a consequence."

Might-o'chondri-AL said...
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MM said...

For any who are interested, here's a paper on the polyphenol content of selected foods and a discussion of the bioavailability.

http://www.ajcn.org/content/79/5/727.full

Might-o'chondri-AL said...
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Laura said...

A cursory search leads me to believe that oleanolic acid can be found in garlic and ursolic acid in many sources including sage. If Al would care to comment, I'd appreciate it. These are already in my diet in significant amounts (unrelated to this blog's purpose...)

Might-o'chondri-AL said...
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mike27 said...

M-Al: Why don’t you get your own blog going? You’re hijacking health blogs all over the internet!

Might-o'chondri-AL said...
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Anna said...

@ Mighty-Al,

As a l-o-n-g time reader of Stephan's WHS blog and occasional commenter, I don't mind your comments at all. You are not argumentative or nitpicking, and it seems you genuinely aim to add substance to the thread. And like one other reader said a while back - you are certainly mysterious.

I just truly don't understand most of your comments. I didn't pursue a lot of science in my education but I find it interests me very much now. I've picked up enough knowledge to comprehend the gist of expert comment on the science-oriented blogs I read. But I have to skip over a lot of your comments, and I wish I didn't have to. I guess this is where I should insert, "it's me, not you", right?

Is there any way for you to dumb it down a little for us mere mortal readers? ;-) Not only is the terminology you use over my head, I don't always see even the context or connection to the topic. From what a few other readers have said about your comments, I'm guessing I'm not alone. I doubt anyone who reads this blog regularly is completely scientifically illiterate, but I'm sure isn't a trained scientist, either. Maybe Stephan can entertain the idea of preparing a survey to measure the scientific literacy of his readers, as a matter of interest, not competition ;-) ).

Don't mean to offend, but since you are trying to share your considerable knowledge with the other readers, it looks like you are missing a lot of targets. Perhaps you could find a way to adjust the message?

Robert said...

Might-o'chondri-AL

You are doing a great job, and your level and breadth of knowledge is mind numbing.

Those posts must take you quite a while to compose - so very many thanks.

I often do not understand the grit, but get the gist and always have the option to look up unfamiliar terminology etc, so keep doing what makes suits you make you happy, and adds value to Stephan's great blogs. (-: