Fierce Debate over Zeaxanthin Isomers

June 26, 2014

Of all the eye-health ingredients known to dietary supplement shoppers, none is more prominent today than lutein. SPINS ranks lutein as eye health’s top seller, citing double-digit, past-year gains of 13.1% and 16.7% in the natural and conventional channels, respectively. Somewhat lesser known is zeaxanthin, another key eye-health carotenoid. But, although consumers may not realize it, they’re already quite familiar with zeaxanthin. Most supplements that contain lutein also include zeaxanthin. Together, the two work hand in hand to protect the eye against oxidative stress and to help maintain macular pigment optical density (MPOD).

A healthy macular pigment is rich in lutein and zeaxanthin. In the macular pigment, lutein and zeaxanthin absorb harmful, high-energy (blue) light, thereby acting as a filter to protect the macula. Lutein is dominant in the periphery of the macula, helping you see in low-light conditions and reducing glare discomfort. Zeaxanthin primarily concentrates in the center of the macula where it helps with sharp central vision and contrast.

Researchers have invested a lot in lutein and zeaxanthin’s study. Most notably, of course, is the National Institutes for Health’s Aged-Related Eye Disease Study 2 (AREDS2), a 4203-patient, five-year phase 3 follow-up study on the ability of supplements to help slow or delay the progression of age-related macular degeneration (AMD), the leading cause of blindness. An AREDS2 subgroup experienced an 18% reduced risk of AMD progression when lutein and zeaxanthin were added to the original AREDS supplement formula of vitamins C and E, zinc, and copper (but minus the original formula’s beta-carotene). Perhaps even more telling of lutein and zeaxanthin’s effectiveness, subgroup subjects (1,055 eyes) with the lowest lutein and zeaxanthin intake (median 0.7 mg/day) had a significant, reduced risk of AMD progression of up to 26% following supplementation.

This subgroup may better represent the level of lutein and zeaxanthin intake in the U.S. population, says ingredients supplier Kemin (Des Moines, IA). AREDS2 used DSM Nutritional Products’ (Parsippany, NJ) OPTISHARP zeaxanthin, as well as Kemin’s FloraGLO lutein, which DSM formulates.

The body must get lutein and zeaxanthin from the diet or from supplementation. Unfortunately, “In the United States, the dietary intake of lutein and zeaxanthin is typically less than 1-2 mg/day. This amount is well below the 10 mg lutein and 2 mg zeaxanthin that the [AREDS2] study has proven to be effective,” Kemin says.

While AREDS2 results build on the positive support around lutein and zeaxanthin for eye health, a recent report out of France raised some questions about one zeaxanthin isomer.


The French Report

Two zeaxanthin stereoisomers are found in the macular pigment, along with lutein: the 3R,3’R isomer (also referred to as “RR-zeaxanthin”) and the 3R,3’S isomer (also called “meso-zeaxanthin”). A third, less-common isomer of zeaxanthin, 3S,3’S, also exists.

“Isomers are molecules with the same molecular formula but different chemical structure (same number of atoms of each element, but arranged differently in space),” explains Lynda Doyle, vice president, global marketing, for ingredients supplier OmniActive Health Technologies (Morristown, NJ). All of these zeaxanthin stereoisomers share the same number of double bonds and similar end rings; however, the direction of one hydroxyl group differentiates them. According to Doyle, “Most nutrients exist in nature and the diet as stereoisomers and are consumed as such and are safe—for example, proteins, amino acids, and sugars. One such example is alpha-lipoic acid, which is commercially available as a 50:50 racemic mix of the R and S isomers (RS).”

Tatania Emmick, technical service manager at Kemin, cautions, however, that “there are certain cases in which the differences between isomers can be 1) ineffective, 2) effective, but in different ways, or 3) toxic. So, that is why chirality really matters.”

In March 2014, French regulatory division the Directorate General of Competition, Consumer Affairs, and Fraud Prevention (DGCCRF) reported that at least 50% of eye-health dietary supplements on the French market that contain lutein and zeaxanthin are “contaminated with meso-zeaxanthin, an unevaluated isomer of zeaxanthin.”

Meso-zeaxanthin is not an authorized dietary ingredient in the European Union because it does not currently have Novel Food approval. (EU Regulation No. 258/97 states that any food not consumed to a significant degree in the EU prior to May 1997 cannot enter the market without first getting Novel Food approved.)

DGCCRF began investigating eye-health supplements—in part as requested by one trade group, the Zeaxanthin Trade Association—following at least 40 reports of adverse events after consumers took eye-health supplements. These events included adverse skin effects or, as DGCCRF stated in its report, “10 reported undesirable cutaneous side effects that were manifested as ‘toxidermia,’ including eight that were allegedly linked to the consumption of four products containing lutein and zeaxanthin.” The adverse events stemmed from products manufactured by various companies, the report added.

French agents subsequently inspected 27 lutein/zeaxanthin finished-products on the French market and found that 14 of them (50%) contained meso-zeaxanthin. They also conducted site inspections of ingredient suppliers, manufacturers, and retailers.

Although the French report initially associated meso-zeaxanthin with adverse side effects, not everyone is convinced there is a link. “Lutein, RR-zeaxanthin, and meso-zeaxanthin were not the only ingredients in the formulations that reportedly caused toxidermia,” Doyle points out. “Have the authorities reviewed the complete ingredient profile and allergenic potential of the products?” If not, she says, it’s hard to definitely attribute adverse effects to any of these three macular carotenoids, “all of which have such strong safety records.”

Doyle adds that “hundreds of supplements around the world containing varying levels of lutein, RR-zeaxanthin, and meso-zeaxanthin have been on the market for some time, with no reported adverse events” and that, to date, there are no adverse events reported in research studies involving meso-zeaxanthin.

Since its initial report in March, DGCCRF followed up with a statement in May saying that the origin of the reported adverse events remains unclear (DGCCRF is uncertain which molecules in the finished-product formulations were responsible for the adverse effects). Still, it reported that the number of adverse-event reports decreased since the investigation began and DGCCRF contacted the supplement manufacturers in question—many of whom DGCCRF initially reported “either modified their formulas or halted distribution” of their products.


Zeaxanthin Isomers

Meso-zeaxanthin may be under fire in France and may lack Novel Food clearance in the EU, but, in the United States, FDA acknowledged a Generally Recognized as Safe (GRAS) notification for an eye-health ingredient that includes meso-zeaxanthin. In 2011, the agency acknowledged OmniActive’s GRAS notification for Lutemax 2020, which contains lutein, RR-zeaxanthin, and meso-zeaxanthin.

FDA’s GRAS database also shows another, pending meso-zeaxanthin submission, dated August 5, 2013, for a “meso-zeaxanthin rich extract” powder called Hi-Fil Z from Mexico-based carotenoid supplier Industrial Organica S.A. de C.V.

Critics on both sides fiercely argue over the value of meso-zeaxanthin supplementation for eye health, especially when comparing meso-zeaxanthin to RR-zeaxanthin.

RR-zeaxanthin­—also often referred to simply as zeaxanthin—is inarguably the most studied zeaxanthin isomer for eye health. It is GRAS affirmed in the United States. Humans obtain the RR-isomer from foods such as dark green leafy vegetables or yellowy-red fruits and vegetables, as well as egg yolk. In the ingredients market, RR-zeaxanthin’s main commercial sources are marigolds (Tagetes erecta)—which is also the commercial source of lutein—or paprika (Capsicum annuum).

Eye-health ingredient suppliers Kemin and OmniActive each have exclusive distribution deals for RR-zeaxanthin. Kemin’s ZeaONE zeaxanthin stems from the company’s exclusive right to a patented, zeaxanthin-rich marigold plant from Chrysantis (Chicago)/Ball Horticultural Corp. (Chicago).1 OmniActive’s OmniXan zeaxanthin is licensed from Kalsec (Kalamazoo, MI) and comes from pepper/paprika.

A third source of RR-zeaxanthin is chemical synthesis. This is how DSM creates its OPTISHARP synthetic, nature-identical RR-zeaxanthin. FDA had no objections to a New Dietary Ingredient notification for OPTISHARP, which also has self-affirmed GRAS status in the United States as well as Novel Food approval in the EU.

Regardless of whether the RR-isomer is obtained from “natural” sources (marigold or paprika) or is synthesized, “All of the science to date tells you that if you ingest zeaxanthin [RR-zeaxanthin] via supplementation, it’s going to get where it needs to be in the eye, just as it would if you got it from eating food,” says Kemin’s Emmick.