Get Protection with Carnosine and Histidine

Carnosine and Histidine
Offer Unusual Benefits

In addition to their anti-AGE action, they protect against
alcohol-induced liver damage and depression
By Will Block

I read about the evils of drinking, so I gave up reading.
— Henny Youngman

long with sex, scatology, politics, and religion, drinking has provided endless fodder for humorists throughout the ages. Just think of all the jokes that start out, “A guy walks into a bar . . .” It would be easy, and a lot of fun, to fill these pages with nothing but drinking-related jokes and aphorisms, and it’s a safe bet that you would then remember (and perhaps treasure) this issue of Life Enhancement above all others. It’s tempting . . .

But darn it, we’re supposed to be a serious enterprise, and you’re supposed to be a serious reader, with more tolerance for depressing news than Mr. Youngman seems to have had. Your reward for reading about the alcohol-related unpleasantness mentioned in this article will be to hear some good news about how certain common nutrients may help alleviate one of the most notorious effects of excessive drinking: liver damage. (Do not misconstrue this to mean that it’s OK to drink to excess because you might be able to use nutrients to nullify the harm. That is not a viable strategy—sorry.)

The nutrients we’re talking about are histidine (an amino acid) and carnosine; the latter consists of histidine and β-alanine (another amino acid) joined by a chemical bond called the peptide bond. That makes carnosine a dipeptide, a two-amino-acid molecule. A three-amino-acid molecule is a tripeptide, and so forth. (A particularly important tripeptide is the powerful natural antioxidant glutathione, which consists of glutamic acid, cysteine, and glycine. We’ll hear more about glutathione later.)

Alcohol Causes Liver Damage via Oxidation and Inflammation

Alcohol-induced liver damage can culminate in cirrhosis, an inflammatory, degenerative condition in which the function of liver cells is impaired and blood flow to the liver via the portal vein is obstructed. These problems often lead to jaundice, ascites (abdominal dropsy, an accumulation of serous fluid in the peritoneal cavity), and liver failure. It’s not a pretty picture.

The liver is alcohol’s primary victim because that is where alcohol is metabolized, via three major biochemical pathways. All three entail the generation of reactive oxygen species (ROS), whose cumulative, deleterious impact on our system is called oxidative stress. Many ROS are free radicals, which are molecules that have an unpaired electron, making them highly reactive and hence potentially harmful.

A key player in the oxidation of ethanol (ethyl alcohol), and hence in the oxidative stress it produces, is a protein called CYP2E1, which is a member of the large family of enzymes called cytochrome P450. This particular cytochrome is known to induce liver damage through its activation of toxic and reactive products, including the highly destructive hydroxyl radical (HO·).

Oxidative stress is at least partially responsible for another manifestation of alcohol-induced liver damage, namely, inflammation (a phenomenon that underlies many diseases and conditions). It is well known that oxidation and inflammation are closely related in living organisms, and their interrelation facilitates the progression of degenerative diseases. In the case of ethanol toxicity, the inflammatory damage is attributed mainly to two proteins, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which can lead to various types of dysfunction and even the death of liver cells.

Carnosine and Histidine Are Antioxidative and Anti-Inflammatory in Diabetic Mice

From the above, it would seem that any substance that could prevent or alleviate oxidative stress or inflammation in the liver might be useful in mitigating the damage done by excessive alcohol consumption. Enter carnosine and histidine, which are known from a study by Taiwanese scientists to provide both antioxidative and anti-inflammatory protection against diabetic deterioration in mice.1 Let’s first review that study, which stimulated the researchers’ interest in the alcohol problem.

The researchers found, first of all, that in diabetic mice, supplementation with carnosine and histidine increased the levels of these two compounds in the blood and tissues. That might seem like a no-brainer, but in fact, it’s not. One can never assume that supplementation with a given substance will increase its blood or tissue levels—whether in healthy organisms or diseased ones—because there are many ways in which this effect can be thwarted. Thus, experimental evidence is required.

More importantly, the researchers also found that both carnosine and histidine (added to the animals’ drinking water at a concentration of 1 gram per liter) produced the following significant changes:

  • Decreased glucose (blood sugar) levels. The widespread damage done to the body’s tissues and organs in diabetes is initiated by high glucose levels. Among the characteristic consequences of this condition is an accelerated rate of glycation, a harmful process in which glucose reacts destructively with proteins, lipids, and nucleic acids, leading to the formation of advanced glycation endproducts (AGEs). These aptly named entities, most often encountered in the form of pathologically cross-linked proteins, tend to foul the molecular machinery of life.*

  • Decreased fibronectin levels. Fibronectin is an extracellular matrix protein whose levels are known to be increased by oxidative stress associated with high glucose levels.

  • Increased insulin levels. Diabetes had been induced in the mice with the drug streptozotocin, which damages or destroys the pancreas’s beta cells, where insulin is produced.

  • Decreased triglyceride (fat) and cholesterol levels in the heart and liver. (They were probably decreased elsewhere too, but the heart and liver were the only organs tested for these substances.)

  • Increased catalase and glutathione peroxidase activities in the liver and kidneys (and probably elsewhere). Catalase and glutathione peroxidase are two of the body’s most important antioxidant enzymes; the antioxidant activity of the latter depends critically on the presence of the potent nonenzymatic antioxidant glutathione as a cofactor.


Normal liver and cirrhotic liver

  • Decreased malondialdehyde levels. Malondialdehyde is a product of the oxidation of lipids, a process that occurs under oxidative stress and that contributes greatly to the development of atherosclerosis.

  • Decreased levels of IL-6 and TNF-α, the proinflammatory proteins mentioned above.


*For recent discussions of the importance of AGEs in disease and aging, and how to combat them, see “How and Why to Prevent AGE Damage” (March 2008) and “Benfotiamine Counteracts the AGEs in Your Meals” (May 2008).


Carnosine and Histidine Suppress Oxidation and Glycation of Human LDL

In addition to the mouse results, the researchers included in their paper the results of experiments conducted on blood taken from 15 young (aged 21–28) human males who had no diabetes-related inflammatory or vascular diseases. In the laboratory, they used glucose to induce both oxidation and glycation of the men’s LDL (low-density lipoprotein). This is the lipoprotein that carries cholesterol in the blood and is commonly called LDL-cholesterol (the “bad cholesterol”). Both carnosine and histidine significantly suppressed the oxidation and glycation of LDL.

From all the results described above, the researchers concluded that carnosine and histidine might prove (upon further research) to be effective supplements against the development of diabetes and the consequent deterioration of bodily functions. The antioxidative and anti-inflammatory properties they observed in these substances suggested the possibility that they might be useful against the effects of alcohol as well.

How to Help a Drunken Mouse

In a newly published study, the Taiwanese researchers examined the effects of carnosine and histidine in young male mice in which they induced chronic liver damage by giving them ethanol 4 times a week for 4 weeks.2 The control mice were given a harmless maltose solution of equal caloric value so that effects due to energy metabolism and weight gain could be ruled out. These mice also received carnosine and histidine so as to establish a baseline for comparison for any effects of these substances on liver function.

The carnosine and histidine were administered in the animals’ drinking water (at 0.5, 1, and 2 grams per liter) for 3 weeks following the 4-week ethanol “binge.” Thus, the study was designed to evaluate the post-treatment effects of these agents on established liver damage—a tough test! (It would have been interesting to see what the effects of carnosine and histidine might have been if they had been administered before or during the ethanol treatment.)

Carnosine and Histidine Alleviate Liver Damage

The results were remarkable. The carnosine and histidine post-treatment significantly reduced the levels of: ALT and AST (two enzymes whose concentrations are markers for liver toxicity); CYP2E1 (the liver-damaging enzyme mentioned earlier); malondialdehyde; IL-6 and TNF-α; and CRP (C-reactive protein, a marker of inflammation and various degenerative diseases, especially those involving blood vessels). Some of these beneficial changes were undoubtedly related to the significant increases in three other substances measured: the antioxidants glutathione, glutathione peroxidase, and catalase.

The authors concluded,2

. . . chronic ethanol administration caused hepatotoxicity [liver toxicity] including oxidative and inflammatory injury. The post-intake of histidine and carnosine provided both antioxidative and anti-inflammatory activities and effectively alleviated alcoholic hepatotoxicity. . . . These results suggest that these two compounds could be considered as effective agents for alleviating chronic alcoholic liver injury.

Alcohol Is No Joking Matter

Jokes about drunkenness come easy, but they’re a guilty pleasure because the subject is, of course, deadly serious and very depressing. Of all the substances that are abused in the world, alcohol is the most common—and the results are not pretty. Chronic alcoholism decreases life expectancy by about 15 years. It’s associated with an increased incidence of cardiac arrhythmia, hypertension, stroke, acute hepatitis, cirrhosis, gastritis, pancreatitis, syncope (loss of consciousness), amnesia, neurodegenerative disorders, and personality changes.

Because ethanol (ethyl alcohol) is a rich source of nonnutritive (“empty”) calories, heavy drinking often leads to malnutrition and vitamin deficiency, accompanied by weight gain, which opens its own Pandora’s box of medical demons. Good grief!

Grief (not good) is the dark shadow that hovers over everyone who overindulges. Apart from liver damage and all the other medical problems listed above, alcoholics suffer—and inflict—countless other forms of harm and havoc. Emotional disturbances, irresponsible spending, antisocial behavior, traffic accidents, birth defects, spousal abuse, child abuse, family breakups, homicide, suicide, . . . there’s no end to the damage caused by “demon rum” when it’s abused.

To make matters worse—indeed, much worse—alcohol abuse is often accompanied by addiction to nicotine and other dangerous drugs. In about 40% of alcoholics, there was a pattern of inappropriate drinking or other substance abuse before the age of 20. In other words, such youthful bad behavior is a pretty good indicator that it will persist into adulthood in one way or another. And that, of course, presages a life made short and miserable compared to what might have been. What a tragedy.

Chances are good that your life has been touched by alcohol abuse in some way, even if only indirectly. About 30% of American adults drink to excess at least occasionally, and 10% of men and 3–5% of women are chronic abusers. Common symptoms of alcohol dependency are solitary drinking, drinking in the morning, lying about the extent of one’s drinking, and maintaining hidden supplies of beer, wine, or booze. If you know someone who fits this pattern, please try to help them—it could save their life.

A final thought: on-the-job impairment. Do you really want to purchase goods and services provided by people whose ability or judgment is impaired by alcohol or mind-altering drugs? For two dramatic, life-and-death examples, think of pharmacists and airline pilots. But what about assembly-line workers, accountants, electricians, bridge inspectors, auto mechanics, meat packers, toy makers, etc.? For that matter, what about . . . medical writers? (I’m sober, I swear.)

Rats! This Is Depressing

As usual, we must be mindful of the possibility that results observed in mice may not translate well to human beings; only studies with real people can tell that tale. But do not be depressed by this—and if you are, perhaps the results of another study will help cheer you up. Researchers in Japan had reason to believe that carnosine might have an antidepressant effect, so they tested this hypothesis, using not just carnosine but also a commercially available supplement, chicken breast extract (CBEX), which is rich in carnosine.3


“. . . histidine and carnosine provided
both antioxidative & anti-inflammatory
activities and . . . could be considered
as effective agents for alleviating
chronic alcoholic liver injury.”


The study was done not with humans but with rats. But what do rats have to be depressed about, and how could you tell in any case? The answers are amazingly simple. First, you place the rat in a steel bucket painted black and partially filled with water so the rat has no way out and is forced to swim aimlessly, seeing and feeling nothing but the black, featureless wall. That’s pretty depressing for a rat (you probably wouldn’t like it either).

And to tell how depressed the rat is rendered by this hopeless situation (which lasts for 15 minutes), you measure the rat’s “immobility time,” defined as the time spent not swimming but simply floating motionless or treading water enough to keep from drowning.

This “forced swimming test” is one of the most frequently used methods for screening for the efficacy of antidepressant drugs in animals, before they’re tested in human clinical trials. (You see? Not everything has to be high-tech these days.)

Carnosine Made the Rats More Hopeful (Apparently)

In the trials with CBEX, there was a dose-dependent tendency toward an antidepressant effect in the rats—i.e., they spent more time swimming and less time immobile—but it was not statistically significant. With carnosine alone (administered in amounts equivalent to those found in the CBEX), the same tendency was seen, but it was statistically significant: the critters presumably had more hope in their little hearts as they swam for their lives.

The researchers also measured the levels of certain monoamines and their metabolites (seven compounds in all) in the rats’ brains after they were killed. No changes were seen except in one of them, a compound called MHPG, which is a major metabolite of noradrenaline (norepinephrine); its levels tend to rise during some stress conditions, owing to increased release of noradrenaline. In the study, the levels of MHPG were significantly reduced by both CBEX and carnosine, suggesting that these agents have the ability to reduce stress induced by forced swimming.

Histidine Probably Played a Role

It was known from a previous mouse study that histidine (one-half of the carnosine molecule, remember?) has an antidepressant-like effect in the forced swimming test,4 and the Japanese researchers speculated that histidine produced by the breakdown of carnosine in the rats might have contributed to the observed benefits.

Orally administered carnosine does break down to its constituent amino acids (histidine and β-alanine) to some degree, and conversely, carnosine is synthesized in our bodies from the histidine and β-alanine that are always there. The balance between these opposing processes under any given circumstances is governed by the laws of chemical thermodynamics, through which all chemical equilibria can be understood. In the Taiwanese study on diabetic mice discussed above, the researchers observed that carnosine supplementation increased histidine levels in the mice, and histidine supplementation increased carnosine levels.1

Try Not to Laugh


Henny Youngman
At the beginning of this article, we said you would be rewarded for your reading of it with some good news about the health benefits of carnosine and histidine. We hope you found the article worthwhile. As a bonus for getting all the way to the end, you deserve an extra reward—and who better to provide it than the irrepressible Henny Youngman?

“My father was never home—he was always away drinking booze. He saw a sign saying ‘Drink Canada Dry.’ So he went up there.”

“My grandmother is over eighty and still doesn’t need glasses. Drinks right out of the bottle.”

References

  1. Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 2005;513:145-50.
  2. Liu WH, Liu TC, Yin MC. Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury. Food Chem Technol 2008;46:1503-9.
  3. Tomonaga S, Yamane H, Onitsuka E, Yamada S, Sato M, Takahata Y, Morimatsu F, Furuse M. Carnosine-induced antidepressant-like activity in rats. Pharmacol Biochem Behav 2008;89:627-32.
  4. Lamberti C, Ipponi A, Bartolini A, Schunack W, Malmberg-Aiello P. Antidepressant-like effects of endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test. Br J Pharmacol 1998;123: 1331–6.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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