Enzymes and Vitamins:  Understanding the active forms of vitamin B12

by Dr. Greg Kelly

Cyanocobalamin is the most commonly supplemented form of vitamin B12, but you might be surprised to discover that this form of vitamin B12 does not actually occur in plants or animal tissues. In other words, outside of the chemically synthesized cyanocobalamin that you encounter as B12 in most vitamin supplements, you would be extremely hard pressed to find this compound in nature (in fact you would not be able to find it). As the name implies, cyanocobalamin contains a cyanide molecule. Most people are familiar with cyanide as a poisonous substance. Although the amount of cyanide in a normal B12 supplement is small and from a toxicology point, viewed as insignificant, your body will still need to remove and eliminate this compound. This removal is accomplished through your detoxification systems with substances like glutathione being very important for the elimination of the cyanide.

Another available form of B12 that offers significant advantages over cyanocobalamin is called methylcobalamin This form of B12 is called a coenzyme form of B12 and is believed to be a much more active form of the vitamin. In addition to the methylcobalamin coenzyme form, B12 is also available in another coenzyme form, which is most commonly called "adenosylcobalamin". The adenosylcobalamin form of B12 is also occasionally called cobamamide or dibencozide. Although methylcobalamin and adenosylcobalamin are both considered to be active forms of B12, they do appear to offer slightly different health advantages. We will discuss those; however, before beginning this discussion it is important to make a distinction between an enzyme and a vitamin, so that you will be able to appreciate the advantage that coenzyme forms of vitamins can offer.

Most people assume that a vitamin has some type of special activity or unique and important function in the body. In essence, there is a degree of correctness and a degree of incorrectness to this basic assumption. The truth is that a vitamin is nothing more than a component of one or several enzymes. And, enzymes are what are important for generating the chemical reactions you need for good health. To the degree a vitamin that you consume in a supplement can be converted into or plugged into an enzyme, the basic assumption will be correct and a vitamin will be able to fulfill its actions in support of your health.

Let's use a metaphor here to try and make this clear. We will resort to a car metaphor since most of you will have a great degree of familiarity with the car and its various parts. Let's pretend that one of the enzymes needed for function of this car is the ignition system. Without the ignition system catalyzing the reaction we call "starting the car", the car has much less usefulness. Enzymes in your body are similar; they are needed to jump-start the various reactions you need to allow for good usefulness of all of your various capabilities and systems.

Now in our car model, if this particular enzyme were the ignition system, what would the vitamin part be? Probably the best way to think of the vitamin would be as the key to the ignition system. Obviously the key is a very important part of the ignition system. However, how valuable is the key without an ignition system? Not very useful actually. In fact, you can have a surplus of keys, but if there is no ignition system, or if part of the ignition system is missing, or if the key is not placed correctly into the ignition system, these keys are in effect utterly useless. Vitamins are very similar to this. If they are not plugged into the enzyme correctly, you can have an abundance or surplus of the vitamin, and you still will not have appropriate function.

There is another level of complexity with respect to vitamins that is also never discussed. Did you know that the common forms of vitamins used in the majority of supplements are actually a far cry from the compound that will eventually be plugged into the enzyme? In other words, the vitamins that you take in a pill have to be processed inside your body (usually in many different steps) to turn the vitamin into something your body recognizes and can then plug into the enzyme. Another way to state this is that your body has to do a bunch of work on most vitamins in order to get any benefit from them. And just as in any other type of work, more different steps from start to finish of a process will create many more opportunities for mistakes to occur.

Let's return to our car metaphor for a moment. In this example, the vitamins that you consume as supplements can best be thought of as a blank key that has not been cut to fit the ignition system. Granted it is the building block for what you will need, but until someone cuts the appropriate grooves and indentations so that it will fit your ignition, it will be unable to catalyze the reaction called "starting the car". Having blank keys available is important, but having a key that fits and is inserted correctly into your ignition system is what is really important. In the automobile world, a locksmith can cut the appropriate grooves and indentations into the key so that it will fit your cars ignition system. In your body, the absorption and transformation processes that occur in your intestines and liver, act as this locksmith.

Some of the many factors that can limit the ability to take a vitamin and turn it into an enzyme include genetic metabolic errors, aging, nutritional inadequacies of other important vitamins and minerals, enzyme defects, disease states (especially of the liver, kidneys or with digestion and absorption), and pathological changes to tissues. In all of these circumstances you can have many blank keys available, but the locksmith just cannot perform the job of cutting the keys and putting them into the ignition correctly.

You might be wondering about food.... what does food have in it? Well, in this metaphor, food contains the complete ignition system with the perfectly fitted key already inserted in the ignition system. In other words food contains vitamins already in the form needed for the enzyme to work and already appropriately placed into the enzyme. Obviously this is an advantage when compared to just having a blank key.

The other option for vitamin supplementation is to supplement with coenzyme forms of vitamins. A coenzyme form of the vitamin means the key (or vitamin) has already been cut to fit the ignition perfectly, so it bypasses the need for the locksmith. Vitamin B12 offers two such coenzyme forms, methylcobalamin and adenosylcobalamin.

Compared with cyanocobalamin, it appears that both methylcobalamin and adenosylcobalamin are better absorbed and retained in higher amounts within your tissues. In simple terms, they are used much more effectively. In general, methylcobalamin is used primarily in your liver, brain and nervous system, while adenosylcobalamin is used mostly in the liver and for hemoglobin (blood cell) production

One of the classic indications of B12 deficiency is a specialized form of anemia called macrocytic anemia. This usually shows up on a lab test as an increased mean corpuscular volume (in other words your blood cells are a bit larger than they should be). While iron is often the only thing given for anemia, this form of anemia usually has nothing to do with a lack of iron. B12 and folic acid are the nutrients you would need, but you need them to be plugged into enzymes. Because of this, the active forms of B12 are often much more effective. Even with other forms of anemia, it is usually much more effective to combine iron supplementation with folic acid + either or both of the active forms of vitamin B12.

In animals, a significant body of experimental evidence suggests that a deficiency of vitamin B12 can enhance the activity of various carcinogens. Animal experiments have also demonstrated that both methylcobalamin and adenosylcobalamin increase survival time and reduce tumor growth in some forms of cancer. Amazingly, methylcobalamin has also been shown to enhance the effectiveness of methotrexate, a drug sometimes used in the treatment of cancer. The active forms of B12 also appear to be very important in supporting proper immune system health. While this information should not be presumed to apply to human cancer, and their is currently no available evidence indicating that any form of vitamin B12 has any benefit in preventing or treating cancer, it certainly seems that this nutrient would be worthy of some future research.

Methylcobalamin is the specific form of B12 needed for nervous system health. Because of this it should be the first form of this vitamin thought of when interested in attempting to optimize the health of the nervous system with vitamin supplementation. Indications of a potential deficiency of B12 in the nervous system might include numbness, tingling, loss of feeling sensation, burning sensations, muscle cramps, nerve pain and slowness of reflexes.

The relative balance of the nervous system is also of critical importance in your overall sense of health and well being. In essence we have a fight or flight nervous system and a relaxation nervous system. Methylcobalamin has been shown to be an important vitamin in helping to establish and maintain an appropriate balance between these two opposing nervous systems.

Because of methylcobalamin's importance in nervous system health, it is also an important nutrient for vision. In fact, continued visual work (like work on a computer) often leads to a reduction in something called "visual accommodation". Methylcobalamin can significantly improve visual accommodation, while cyanocobalamin appears to be ineffective.

An elevated level of homocysteine is a metabolic indication of decreased levels of the coenzyme forms of vitamin B12, especially methylcobalamin. Homocysteine has received a tremendous amount of emphasis in the scientific literature because of its associations with heart disease and a variety of other specific health conditions. I have even seen advertisements on television promoting folic acid, as a vitamin needed to lower homocysteine. While this is true, and folic acid does lower homocysteine levels, the combination of methylcobalamin and folic acid appears to work much better.

In people with liver disease, although high blood levels of vitamin B12 are common, it is not unusual to actually have a correspondingly low liver tissue concentration of vitamin B12 and its enzymes. In effect your locksmith can't make keys anymore so the functions that depend on a complete and working B12 enzymes often suffer. Because of this, methylcobalamin and adenosylcobalamin should be the forms of B12 used under these circumstances. In fact, even under normal circumstances, the active forms of B12 help the liver function much more efficiently. Liver detoxification and antioxidant systems work much more effectively when methylcobalamin and adenosylcobalamin are supplied (as opposed to cyanocobalamin). Since our livers tend to be over worked due to the varieties of pollution and other environmental factors we are exposed to, these active forms of B12 can be valuable forms of additional nutritional support for the liver.

The most well studied use of methylcobalamin has to do with sleep. Although the exact mechanism of action is not yet clear, it is possible that methylcobalamin is needed for the synthesis of melatonin. Available information indicates that methylcobalamin can modulate melatonin secretion, enhance light-sensitivity, and normalize circadian rhythm (your 24-hour clock). Because of this, individuals supplementing this form of B12 often have improved quality of sleep, often will require slightly less sleep, and will not uncommonly report that they feel a bit more refreshed when waking in the morning. Methylcobalamin is particularly effective when your 24-hour clock is not running smoothly. This may be indicated by a need for excessive sleep, changing sleep-wake cycles, or a tendency to have altered sleep wake patterns. As examples, you might require 10-12 hours of sleep, or you might not feel tired until 2-3 am and you might wake at noon, or you might find that you wake a bit later every day and go to be a bit later every night. Under all of these circumstances the combination of methylcobalamin (about 3000 mcg daily) and exposure to bright light in the morning can help reestablish your 24-hour clock.

Because of methylcobalamin's impact on 24-hour clock and the cycles that feed of this, it is also an important vitamin to regulate your 24-hour release of the stress hormone cortisol. This seems to be particularly important for blood types A and AB. Methylcobalamin also seems to result in a better 24-hour maintenance of body temperature. Typically individuals supplementing this coenzyme form of B12 have higher temperatures in the later hours of the daytime. This usually corresponds with improved alertness at the same time of the day. While this can be of importance to all blood types, low body temperatures seems to be an area of greater challenge for A's and B's.

The appropriate dose of the coenzyme forms can vary, but a dose of between 1000-2000 mcg daily is usually adequate. If attempting to influence sleep cycles or your 24-hour clock a higher dose of methylcobalamin (3000 mcg daily) is usually a more prudent starting point. Both of these forms of B12 are considered to be exceptionally safe and can be used by all blood types.

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