Researcher explains role of enzymes, sugar alcohols in some liver cancers
[00:00:00] Host Amber Smith: Upstate Medical University in Syracuse, New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Commonly used sweeteners can cause cancer of the liver, according to research conducted recently at Upstate. I'm talking with the lead author of that study, Dr. Andras Perl. He's a SUNY Distinguished Professor and also the division chief of rheumatology at Upstate. Welcome to "The Informed Patient," Dr. Perl.
[00:00:33] Andras Perl, MD, PhD: Thank you Amber. It's nice to be with you.
[00:00:36] Host Amber Smith: You and your colleagues published your research in the journal, Nature Metabolism, and I wonder what the response has been like from other scientists. Is this the first paper to show that sugar substitutes can cause liver cancer?
[00:00:52] Andras Perl, MD, PhD: This is the first paper, and we were, ourselves, surprised how effectively we could block the development of cancer by eliminating the sugar from the blood and other tissues of these mice. But this also has relevance for human subjects.
[00:01:12] Host Amber Smith: Have scientists suspected this connection for a while, and have they been looking for proof of this, or is this something brand new?
[00:01:21] Andras Perl, MD, PhD: This is brand new. I have been suspecting this for a long time, and we uncovered many, many years ago that these sugar alcohols accumulate in mice and human subjects that lack this enzyme. And we uncovered that this human subject developed liver disease.
First, we found it in mice, that 50% of mice that lacked the enzyme had liver cancer. And subsequently, human subjects, mainly children, were found to develop a very aggressive liver tumors who had this enzyme deficiency, but nobody directly linked the accumulation of the sugar alcohols to cancer.
We also uncovered another enzyme called aldose reductase is highly overexpressed. We did know that aldose reductase generates the alcohol from the sugars that accumulate in the absence of transaldolase. So we published a paper on the subject that transaldolase deficient mice developed liver cancer in 2009, which was 14 years ago. And in this paper we showed that sugar alcohols accumulate in these mice, and this other enzyme, aldose reductase, is also overproduced in the mice. And later on, human subjects were found that also lacked transaldolase and developed liver cancer, but they were unsure whether the accumulation of the alcohols was actually driving the cancer.
We suspected that the overactivity of another enzyme was contributing to the accumulation of the sugar alcohols. So then, to find out whether this other enzyme contributed to the development of cancer, we generated mice that lacked both enzymes, both aldose reductase and transaldolase, and those mice did not develop cancer, and they did not accumulate sugar alcohols.
So this other enzyme, aldose reductase, converts the sugars that accumulate in the absence of transaldolase. The other enzyme converts them to sugar alcohol, and that apparently is highly carcinogenic. That's what we discovered in mice, but this also applies to humans because humans who lack transaldolase also accumulate these sugar alcohols to the same degree as mice do.
[00:03:54] Host Amber Smith: I want to ask you some more specific questions about your work, but when a finding like this comes out and is published in a prestigious journal like this, do scientists congratulate one another, or are you more competitive?
[00:04:10] Andras Perl, MD, PhD: That's a good question. I did get a few congratulations, but not too many, but maybe others expected this to happen, or I don't know what they think. The question is actually interesting.
[00:04:23] Host Amber Smith: Well, please tell us more about how your study was designed. What sweeteners did you focus on?
[00:04:31] Andras Perl, MD, PhD: We did not focus on sweeteners specifically. We knew that these alcohols accumulated in these mice. And, we suspected that the generation of the alcohols was mediated by the other enzyme aldose reductase, which was over-produced.
And we thought that these, the accumulation of the sugar alcohols contribute to the disease, but we didn't know if it was contributing to the cirrhosis that prevents cancer or it was also contributing to cancer. We only found this out when aldose reductase was inactivated, and the mice no longer made the alcohols and they no longer developed cancer.
So that indicated to us that these alcohols actually, the sugar alcohols, induced cancer. Subsequently, we also treated cells in vitro cancer cells, and we found that they highly over-proliferate if you treat them with sugar alcohols in vitro. So the sugar alcohols themselves induced cancer cell proliferation. We also used inhibitors of aldose reductase, not just genetically inactivated it, but treated cancer cells with drugs that can inhibit this enzyme and they inhibit the proliferation of cancer cells.
So we do know that not only genetic inactivation of the enzyme can prevent cancer, but very, very likely inhibiting the enzyme with drugs can also inhibit cancer formation.
[00:06:06] Host Amber Smith: So these two enzymes that you keep mentioning -- the transaldolase and the aldose reductase -- do healthy people have both of these enzymes in ample supply?
[00:06:19] Andras Perl, MD, PhD: Yes. Normal people have both of these enzymes in ample supply, and one can imagine that through the generation of sugar alcohols, aldose reductase could contribute to cancer formation.
On the other hand, transaldolase protects from cancer, so individuals who lack transaldolase develop liver cirrhosis and cancer. So this enzyme protects from liver disease.
And we also uncover that this enzyme also protects from Tylenol-induced liver failure, which is the leading cause of acute liver failure in humans. We found in another study that people who develop liver failure due to Tylenol overdose, a great percentage of them lack transaldolase, at least, one allele of the enzyme is mutated in those individuals. So this enzyme deficiency also predisposes to Tylenol-induced liver failure, and inactivation of aldose reductase also protects from Tylenol-induced liver failure in mice. So we can presume that in human subjects who develop liver failure due to Tylenol overdose, inhibiting aldose reductase may also be helpful.
[00:07:38] Host Amber Smith: This is Upstate's, the Informed Patient Podcast. I'm your host Amber Smith. I'm talking with physician scientist Dr. Andras Perl. He's a SUNY Distinguished Professor who led research recently that showed how sweeteners can cause liver cancer.
So what do these sugar alcohols do that leads to cancer of the liver? And I know that it involves the enzyme as well...
[00:08:03] Andras Perl, MD, PhD: So sugar alcohols, we don't know exactly how they cause cancer, to answer your question flatly, but we have some suspicions what they might do.
Sugar alcohols create osmotic pressure in the cell. When the cells are exposed to alcohols rather than sugars, they cannot be metabolized, not as readily as sugars, and the alcohols themselves cause osmotic pressure that turn on genes that mediate cell proliferation.
So one of these genes are called "junk," or J N K. So these genes promote DNA replication and cancer proliferation. So I think the osmotic pressure that they create is what drives carcinogenesis. This is a very crude answer, and much more details need to be discovered.
[00:09:02] Host Amber Smith: Would this only be a concern in the case of that J N K gene?
[00:09:08] Andras Perl, MD, PhD: So this junk gene, or J N K, is involved in most cancers. So it is possible that activation of these genes, through osmotic pressure, contributes to many forms of cancer. In fact, in our paper we showed that inhibiting aldose reductase also blocks the proliferation of breast cancer cells. So this mechanism of enhanced carcinogenesis by sugar alcohols may not be limited to liver cancer.
Our model was limited to liver cancer, but this mechanism may apply to other forms of carcinogenesis.
[00:09:47] Host Amber Smith: And the sugar alcohols we're talking about are found in sorbitol and erythritol?
[00:09:54] Andras Perl, MD, PhD: So sorbitol and erythritol are sugar alcohols, and these accumulate in the absence of transaldolase. There is one additional alcohol that we detected highly, which is highly accumulated, called sedoheptulose, which means that it has seven carbons that make up the sugar. Carbon is coal. The main ingredient of coal is carbon. That's an atom. And the sedoheptulose has seven. The sorbitol molecule has six carbons. Erythritol has four carbons. And these carbons are actually formulated in our body by a pathway called the pentose phosphate pathway. And that's where these two enzymes are functioning in our body. The aldose reductase and the transaldolase are a part of this pathway that generates sugars that contain various numbers of carbon atoms. So the erythritol, which is used as a sweetener very commonly, or sorbitol, have four or six carbons.
[00:11:00] Host Amber Smith: So these sweeteners which are on the market and are in different products now, do you think the FDA (Food and Drug Administration) needs to reconsider whether these products containing these should be sold?
[00:11:14] Andras Perl, MD, PhD: Absolutely. So the reason that they found them to be safe is that they cannot be detected in normal individuals. But they have not been measured in a tumor environment, so nobody knows to what degree they are available in tumor environment. And from our study, it's very clear that a very high level of them drives cancer.
Whether or not consuming these sugar alcohols can achieve that concentration anywhere in our human body is a matter of further discovery. It's unknown whether these concentrations that we detected in our transolodase deficient mice can occur in human beings who just consume these sweeteners. But, one can assume if somebody has a predisposition, that will be greatly enhanced by consuming these alcohols. So whoever is drinking these sugar alcohols is taking on a greater risk of cancer development.
[00:12:21] Host Amber Smith: Well, compared with artificial sweeteners, does regular sugar, does that pose a threat to the liver the same way?
[00:12:29] Andras Perl, MD, PhD: The quick answer is yes. It turns out that sugars, especially refined sugars like glucose, for example, support cell proliferation in a much robust and potentially toxic way than other carbohydrates or, for example, fat.
Fat can be burned much more effectively through mitochondria than sugars, which tend to preferentially go into glycolysis, which is, a pathway more commonly used by cancer cells. Sugars in general are not healthy, and they support -- at least in the liver -- potentially abnormal growth.
On the other hand, we do need sugar for the brain to work. Our brain cells depend on sugar. That's the main source of energy for brain cells. So, deprivation of humans from sugar or sources of sugar is probably not something that we should aim for. But limiting sugar might be helpful in general, especially thinking about liver cancer.
[00:13:40] Host Amber Smith: Now your work on this particular study was done in laboratory mice, so I wonder is it going to be replicated in humans at some point?
[00:13:49] Andras Perl, MD, PhD: Some of some aspects of this work has been conducted in humans. So, others have measured the sugar alcohols in patients who lack transaldolase, and they highly accumulate. They also accumulate in human who develop liver cancer and lack transaldolase. So very clearly this is present in subjects who have liver cancer and transaldolase deficiency.
Nobody has studied the expression of aldose reductase in these individuals. However, aldose reductase is known to be overexpressed in all kinds of liver cancers, including those where transaldolase is not deficient.
So the overexpression of aldose reductase is very clearly a driver of liver cancer outside the deficiency of transaldolase. So inhibiting aldose reductase could be a very general mechanism of blocking liver cancer in general. And if we believe that that inhibits cancer, the mechanism of that involves diminished production of super alcohols.
So I must say that sugar alcohols drive liver cancer in general, probably outside transaldolase deficiency.
[00:15:10] Host Amber Smith: After seeing these results, have you and your colleagues removed things from your diet that contain added sweeteners?
[00:15:18] Andras Perl, MD, PhD: Actually, one of my technicians in the lab -- his name is Joshua Lewis, and he greatly contributed to this work because he is genotyping these mice -- told me last week that he actually tried to lose weight. He actually is relying on sugar alcohols. And he has many friends that he's chatting with on the internet, and they use sugar alcohols for achieving weight control, which may work at this potential cost. So I believe that he will be removing this from his diet.
I personally have not used sugar alcohols not at least knowingly. But I believe that people should cut this out of their diet now.
[00:16:01] Host Amber Smith: Well, Dr. Perl, thank you so much for making time for sharing this with us.
[00:16:05] Andras Perl, MD, PhD: Thank you so much for having me, Amber. Thank you.
[00:16:09] Host Amber Smith: My guest has been Dr. Andras Perl. He's a SUNY Distinguished Professor and the division chief of rheumatology at Upstate. He also teaches and does research in biochemistry and molecular biology and microbiology and immunology. "The Informed Patient" is a podcast covering health, science, and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at upstate.edu/informed. This is your host, Amber Smith, thanking you for listening. "