In Search of a Carotenoid Complex

First, all things beta carotene and family of carotenoids have known impact. Important reference >ref

Does your Multiple Vitamin provide both vital beta carotene forms or just one? This is a controversial topic> ref

The simple pieces:

• The Carotenoid complex includes many different members. Chief among them include: Alpha Carotene, Beta Carotene, beta-crytoxanthin, lycopene, lutein, astaxanthin, and zeaxanthin
• Beta carotene comes in a few different forms. 
• The chief two are all-trans beta carotene and 9-cis beta carotene. 
• Both of these forms can split to become vitamin A. The ratio used to be thought as 6 to 1, but now is up to 28 parts beta carotene making one vitamin A. Each vitamin A form takes the same formulation of beta carotene it came from as retinoid or retinoic acid, all-trans or 9-cis retinoic acid. 
• There are receptors for each of these two retinoic acids in cells, RAR for all-trans and RXR for 9-cis.
• Both of these two receptors are needed for many vital body functions. ref <This reference talks about brain health.
• The body uses all-trans to be the dominate form and it remains measurable longer, but without just the right amount of 9-cis present, some body functions could be compromised. ref <9-cis on atherosclerosis
• Since Mother Nature knows diets vary, body adaptations developed to counter those times when one or another of these nutrients might be deficient. The different forms of beta carotene can be converted into other forms. The question is at what amounts?
• Studies show 9-cis is more likely to convert to all-trans then the other way around.
• And yes, the 9-cis form is cleared from blood serum faster. This could represent a move into tissues where it is needed to combine with vitamin D and perform vital connections.
• One study showed 9-cis had higher protective factors to limit peroxidation than all-trans beta carotene, and this could be one of the reasons it disappears faster. ref
• Foods exist that supply many of the different carotenoid forms found in human blood plasma that have health benefits. Future research may find more.
• The majority (over 97%) of multivitamins only contain one form, the synthetic all trans-beta carotene. When Beta Carotene is listed in Vitamin label box as Beta Carotene without any source mentioned, it is usually synthetic.* ref 
• The issue is not that the synthetic form of all-trans beta carotene does not work, it is the absence of the other forms that represents possible issues. 
• For active Vitamin D actions, it has to first combine with VDR, plus RAR, and RARE (elements inside cells) before vitamin D functions occur. Part of this combination needs to combine with RXR to stimulate genes to build proteins such as osteocalcin that accomplish functions attributed to vitamin D. Osteocalcin is responsible for blood sugar maintenance, cancer prevention, plus after activated by vitamin K2, bone building mineralization.
• Beta Carotene and it's pathway formed elements, like all-trans and 9-cis, have cholesterol related functions of improving HDL cell cholesterol attachments to speed elimination of cholesterol. 9-cis BC predominates here over all-trans BC. ref
• This beneficial influence of 9-cis Beta Carotene on cholesterol removal by HDL appears to inhibit atherosclerosis by limiting plaque growth.
• It appears that while all-trans is the dominate lignand for RAR with many vital functions, some RXR from 9-cis is needed to play a balancing role on and with RAR receptors, plus it also has a few vital functions by itself.
• 13-cis retinoic acid is also present in natural sources. It has some vital roles as well, it was approved in 1982 by FDA for use to reduce acne, but is best in secondary roles to not upset balance points with the other retinoids. 
• BOTTOMLINE:  Science needs more research to settle the issues raised by this article. Until then, the precautionary approach takes center stage. Find multiples with a natural source beta carotene like D. Salina algae to get the different carotenoid forms and let the body decide how to allocate and use them. This is especially true for those who do not consume enough vegetables and furits.

HEALTH FACT: Carotenoids in food are more effective than beta carotene supplements. ref The goal then is to find a carotenoid supplement that closely mimics the ratios and synergism between the different carotenoids found in food. Since food can vary in the amount of carotenoids present by many times, there is a narrow window of dosages for supplements that will fit with the related and beneficial elements in food to enhance the carotenoid benefits without upsetting natural body processes. EAT MORE VEGETABLES AND FRUITS, and take low dosages of natural source carotenoid complex supplements.

The body can convert Beta Carotene into vitamin A as needed. article article Today, Beta Carotene is found in most Multiple Vitamins. Vitamin A used to be in all multiple vitamins until toxic actions were discovered such as increasing bone fractures. Natural Beta carotene does not exhibit this effect. BUT, over 95% of multiples contain the synthetic form of only all-trans-beta carotene. In nature, there are 4 different forms of beta carotene, 2 major, all trans- and 9-cis, and 2 minor 11-cis and 13-cis.***  Plus the carotenoid family includes many other members such as alpha carotene, beta-crytoxanthin, lycopene, lutein, astaxanthin, and zeaxanthin. You will not find many Multiple vitamins that include any of these other Carotenoid family members similar to their distribution in many vegetables and fruits. Check out this study. Doesn't this information provide ammo to consume the whole carotenoid complex either in food or from wise vitamin supplements that include many of the natural family factors together such as alpha carotene rather than just Beta Carotene, especially if it is only in the all-trans synthetic form?

THE BENEFITS FROM CONSUMING BOTH BETA CAROTENE FORMS?

Read about the effects of different forms of carotenoids on breast cancer here. (A risk number, OR, under 1 is good and indicates protection with lower risk while over 1 means greater cancer risk. ·0.49 (95 % CI 0·34, 0·71) for lutein/zeaxanthin >represents a low risk) ref

This nutraceutical company website simply describes what is Dunaliella Salina algae, a natural source for Beta Carotene that includes many forms of the other carotinoid complex family members. 

This short reference article (corrupted link removed) clearly explains the differences between natural beta carotene and synthetic beta carotene. Science did not initially spot natural differences until synthetics have been in use for some time, as is the case with synthetic beta carotene.

This scientific article reviews the history of Beta carotene and cancer research. In its own words, a real Dr. Jekyll and Mr. Hyde roller coaster ride.

*SMOKERS taking (synthetic) BETA CAROTENE are in jeopardy

Smokers taking synthetic beta carotene developed more lung cancers than non-smokers in a couple of studies. There is now a better understanding of what might be happening. ref ref  Beta carotene might turn from an anti-oxidant into a pro-oxidant, but that didn't happen in this smoke test tube study on live cells. Beta carotene is highly sensitive to oxygen levels and could change to a pro-oxidant reaction at higher oxygen concentrations, such as in the lungs.  ref  (this reference cuts to the very core of the damaging free radical cause for cancer) From a ferret study, another possibility was found.  

"Extensive conversion of β-carotene to oxidation products was observed in subcellular fractions from smoke-exposed ferrets. β-Carotene also enhanced smoke-induced epithelial cell proliferation and squamous metaplasia. Moreover, carotenoid supplementation also enhanced smoke repression of RARβ expression and enhanced induction of c-Fos and c-Jun. These observations suggest that β-carotene oxidation products may exert effects on retinoid signaling and affect the status of other nuclear transcription factors as well."  

OK, this is just a fancy way of saying that beta carotene might speed up the growth rate of already existing lung cancer cells. What is still open for discussion, would the carotenoid complex achieve a balance over just taking beta carotene as all trans by itself? Is 9-cis needed to balance the all-trans beta carotene form found in 95% of multiple vitamins? Yes, both 9-cis and all-trans retinoic forms are needed for proper function of retinoid signaling, with the 9-cis retinoic form having 9 times greater activity over the all-trans retinoic acid to prevent cancer cell formation. And maybe it is more active since Mother Nature knew she needed more all trans form for so many other vital functions. ref ref

Beta Carotene Factors Revealed

Here are the activation factors at the heart of the beta carotene form controversy. The all-trans form reacts only with the RAR receptor, while the 9-cis form acts with both the RAR and the RXR receptors. Why is this important? RXR is needed to combine with the vitamin D activated VDR to form VDR/RXR to complete vitamin D functions. To support RAR actions, it must first combine with RXR forming the RAR/RXR receptor. The synthetic form of beta carotene containing only the all-trans form is incomplete and that represents a very high probability for why studies are showing adverse or nil effects. Far too many multiple-vitamins only contain the synthetic form of beta carotene.

A study quite some time ago, 2001, found that beta-crytoxanthin levels were the only individual carotenoid family member related to a significant reduced risk of lung cancers in smokers. Higher total carotenoids exhibited a 37% reduction in lung cancer risks for smokers versus those with lower than normal total carotenoid amounts. This study came out of Shanghai, China: PMID: 11440962. ref  For food sources and mechanism of action, go here.    Study Ref

A BALANCED APPROACH 

First, eating vegetables and fruits is the best way to get the many carotenoid family elements. Over 600 forms exist. For those who consume limited vegetables and fruits, it would be prudent to supplement the whole mixed carotenoid complex that appears to have a synergistic ability to limit or avoid this smoke induced reaction found when only taking the synthetic beta carotene form. Dr Weil chimes in here.

This reference article pretty much sums Beta Carotene up. A matter of beginning levels, helpful if low and may not be if already high amounts present. Here are some positive studies on the value of some of the other carotenoids: For Eye health  ref   For Cancer and CVD, ref   For CVD health with alpha ref

Note that Lycopene, a carotenoid from tomatoes, was found significant for influencing cognitive actions.

NOTE: Breast cancer connection may be related to dosage levels of beta carotene. ref and this one. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer - PubMed

And this later follow up study finding alpha carotene had the most impact. ref

 NOTE 2: See** below. Leukemia studies show vitamin D needs 9-cis retinoic acid acting together to prevent. ref

WRAP UP

The take away: Don't take synthetic beta carotene period! ref Take only multiple vitamins containing the whole natural source carotenoid complex such as from Dunaliella Salina algae. This quickly eliminates over 95% of multiple supplements in the marketplace today. How can you tell if beta carotene is from a natural source? The source is listed in the box on the side panel (i.e., D. Salina, or Spirulina). If not listed, it is 99% probably synthetic. Even many whole food type vitamins are mainly just beta carotene with only a small amount of the other carotenoids. Some multiples do list some of the other carotenoid members separately.

Regarding the two different types of beta carotene, all-trans and 9-CIS.  All-trans is considered the more active form and this is why when Scientists created the synthetic form, only all-trans was thought to be needed. BUT, as often happens in nature, the 9-CIS beta carotene excells in some functions. ref  Both forms develop metabolites in the body and turn into all-trans retinoic acid or 9-cis-retinoic acids. In these forms, 9-cis is 10 times more active in preventing neoplastic cell growth, or tumor formation. ref ref But, both retinoic acid forms can also turn into 13-cis and 13-trans.  During pregnancy, these 13- forms may have sinister effects on brain development. It is interesting to note that all-trans retinoic acid turns into 13-cis (ref) more than the 9-cis retinoic acid form. ref 

**IMPORTANT INSIGHT: The hormone or active form of vitamin D attaches to about 30 cell types that have a Vitamin D receptor, VDR, to active genes within the cells to build vital protein structures the body needs for regulation, especially for immunity and to control calcium. At the cell wall, VDR activated by vitamin D, bonds with RXR, from the 9-cis beta carotene now in it's retinoic acid form. It is this combination, VDR-RXR, that influences the genes through DNA to begin the bone building process as well as many other vital body functions. ref

Thus, vitamin D needs magnesium in an enzyme for activation and also vitamin K2, then the hormone form of active vitamin D stimulates VDR that next combines with the 9-cis retinoic acid (from 9-cis beta carotene) activated RXR to complete it's functions in the cell. SYNERGISM! The synthetic beta carotene form, containing only the all-trans form, completely misses out on participating in this RXR pathway with vitamin D activated VDR. Yes, nature often uses back up plans to allow conversion from the all-trans form into the 9-cis form. But it may not be wise to rely on this always happening, especially when the all-trans form has other functions to perform. Consuming vegetables adds to all natural beta carotene forms, but for those that do not like vegetables, be sure to get a multiple vitamin with the natural source D. Salina to get a fuller compliment of carotenoids. 

This is one reason OVER 95% OF MULTIPLE vitamin mineral SUPPLEMENTS available in the marketplace today are NOT ACCEPTABLE according to the NEW VITAMIN CRITERIA?

They only contain synthetic all-trans beta carotene and miss out on all the benefits of 9-cis beta carotene plus the synergistic actions with all carotenoid members. Of course the all-trans form is important too, but many beta carotene functions require both forms to act together. Eating vegetables and fruits, priority one. AVOID THE SYNTHETIC FORM OF BETA CAROTENE.

SIDEBAR: A valid point needs to be highlighted by the issues presented here. When Scientists attempt to study just one or two nutrients, they can miss synergism with other nutrients that may influence the results. As an example, Vitamins C and E levels with their anti-oxidant activity could have possibly mitigated beta carotene results. Plus, cancer cells reacting in a test tube or small animal for the nutrient in question often are not always the same as how cancer cells react in the human body. These concepts make research on vitamins difficult and challenging. And most likely are responsible for contradictory results for the same nutrient from study to study. When questions arise, Scientists should look at how Nature packages nutrients in food. And analyze why? Harmonizing with Nature is probably the better choice rather than trying to control, manipulate, or dominate.

During a virus generated common cold, Nature uses sneezing, coughing, fever, and free radical generation as healing mechanisms to help rid the virus from the body. Are Cold medicines drug and vitamin companies develop working with Nature or against? Is it wise to always work against or might it be more appropriate to first attempt to harmonize with and support natural body immune forces, as long as conditions safe for the body. Many Vitamin issues fall into this situation. Science in the past has decided to work against with limited positive outcomes. And the few apparent short term successes are now showing long term failures, like just calcium for bone fractures.  In this website, you will begin to discover how and why.

*** Clarification for the different forms of Beta Carotene

This is a little confusing, but vital points about the different forms of Beta Carotene and their respective retinoic acid forms increase understanding for supplement choices. All-trans and 9-cis are the two dominate forms in fruits and vegetables. These two forms have the ability to turn into vitamin A as retinoic acid when needed. 9-cis beta carotene not only turns into 9-cis retinoic acid, but can also turn into all-trans and 13-cis retinoic acids. Both all-trans and 13-cis beta carotene turn into mostly only all-trans retinoic acid. Studies have also revealed that the all-trans retinoic acid can turn into 9-cis retinoic acid, but the level of conversion may be compromised under certain conditions and only limited amounts are found in tissues when tested after all-trans ingestion. ref   

SIDEBAR: When Scientists analyze blood levels for the different forms of beta carotenes, they mostly find all-trans. This prompted them to only include the all-trans form thinking that the 9-cis form must be quicly oxidized. Later they discovered that the 9-cis form was found in greater amounts in some organs and tissues, similar to what happens with the other famuly members of vitamin E. 

The 11-cis retinoic acid form gets very little play. It is mostly produced from all-trans retinoic acid and is involved in vision and eye retina light functions. ref 13-cis is very similar in actions to all-trans beta carotene.

Actions of the two dominate retinoic forms are carried out in two ways, either directly, or after they activate nuclear receptors on certain cell walls, including cancer cells. The all-trans retinoic acid only activates the RAR receptor while 9-cis retinoic acid activates both the RAR and RXR receptors. This is a very crucial point. These receptors than combine with another receptor, retinoic acid receptor elements, (RARE) to complete their functions. RAR combines with RXR to form RAR/RXR. RXR can combine with another RXR (RXR/RXR) or a vitamin D receptor, VDR as VDR/RXR, and even a thyroid hormone receptor. Without first combining with RXR, the Vitamin D Receptor, VDR, does not perform its functions. Thus, the importance of the 9-cis form is magnified since it combines with many receptors, as well as RAR. It appears to not be wise to hope enough of the all-trans form will convert into the 9-cis form in adequate amounts since in some studies, it was not present when tested. Of course, both all-trans and 9-cis beta carotene are vital to health. Immune functions, vision, bones, skin, cardiovascular, etc.

TAKE AWAY

It is not necessary to understand all these different forms and actions. The important take away is that nature is a team player. Many nutrients have synergistic actions to balance functions. When Scientist test only one form, sooner or later, adverse conditions can erupt. Like for Vitamin E, and here with beta carotene. A drug form of All-trans retinoic acid, a vitamin A form, at very high dosages has been used to arrest leukemia for over 20 years. BUT, after awhile it stops working and blood levels fall allowing the disease to relapse. The 9-cis form did not develop this resistance. One theory is that without 9-cis present to totally activate the all-trans nuclear receptors, this resistance developed.

DO NOT take large dosages of vitamin A or beta carotene on your own. At certain levels, retinoic acid can generate cellular mutations and increase cell growth. This is one reason why vitamin A is limited to lower dosages. Beta carotene so far has not exhibited these tendencies, but probably best to limit to mainly food sources, eat salads, veggies, and fruits. And for multiples, stay at the lower range of only natural source beta carotene, as D. salina algae, or maybe spirulina. Remember, many multiple-vitamins contain just the synthetic form of beta carotene with only all-trans beta carotene. This form should not be consumed, especially since the Finnish study on Smokers should an increased lung cancer risk.

 PRECAUTION:  Even beneficial nutrients can be overdone. In people who drink a lot of carrot juice, their skin and even the whites of their eyes often turn yellow. This indicates that the liver is not able to process the amount of color carotenoids coming in and places the overflow into out of the way areas until the liver can catch up. This not a desirable action. Another situation where too much carotenoids can also gather, the yellow color elements show up as a ring around the back of the eye. There are definite benefits from a certain intake of carotenoids in protecting the eyes from blue light damage. But, can this too become overdone? More on this soon.

NEW RESEARCH: Obesity linked to low retinoic acid levels. Return soon!