Is all astaxanthin the same?

Astaxanthin has chemical features that result in the existence of several forms of astaxanthin:

Stereoisomers. Astaxanthin has two chiral (pronounced "ky-ral"), or asymmetric, centers. These are the carbons numbered 3 and 3' (pronounced "three prime") on the two rings in the structure. One can think of chiral asymmetry as analogous to "handedness". A left hand and a right hand are mirror images of each other--they are similar but not identical, and are not superimposable. Similarly, a chiral center can exist in either of two configurations; the same atoms are bonded to the chiral center, but the three-dimensional arrangements are different and not superimposable. Chemists identify chiral centers as being either R or S (from rectus or sinister, Latin for "right" or "left"). The two chiral centers in astaxanthin, carbons 3 and 3', can each exist either in the R or the S form, and thus there are a total of three stereoisomers: 3S,3'S, 3R, 3'S, or 3R,3'R. The 3S,3'S and 3R,3'R stereoisomers are mirror images of each other and are termed "enantiomers". Each enantiomer has the opposite optical activity of the other, i.e., a solution of a pure enantiomer will rotate plane-polarized light in a direction opposite to that observed for the other enantiomer. The 3R,3'S form is sometimes termed "meso" and is optically inactive because there is a plane of symmetry through the center of the molecule.

Geometric isomers. Carbon-carbon double bonds can have the atoms attached to them arranged in different ways. This arrangement cannot be changed by the atoms twisting or rotating around the bond (since double bonds are not "flexible" in the way single bonds are) without breaking the double bond. If the two largest groups are attached on the same side (looking down the double bond's length) of the double bond, they are termed Z (from zusammen, German for "together"). If the two groups are on opposite sides of the double bond, they are termed E (from entgegen, German for "opposed"). Older texts may refer to Z as "cis" and E as "trans", however Z and E are the recommended nomenclature today. A double bond may change its geometry from E to Z or vice-versa, but this process requires energy (such as heat) and the breaking and reformation of the double bond. Astaxanthin has several double bonds in the linear portion of the molecule, each of which can potentially exist in the Z or E form. The thermodynamically most stable form of the molecule is all-E ("all-trans") astaxanthin. This is because in the all-E form, the branching methyl (CH₃) groups on the linear portion of the molecule do not compete for space. In nature, Z isomers have been observed at positions 9, 13, and 15, singly or in combination. Thus, several geometric isomers are possible: all-E, (9Z), (13Z), (15Z), (9Z,13Z), (9Z,15Z), (13Z,15Z), and (9Z,13Z,15Z) (Bernhard 1990).

Free or esterified. Astaxanthin has two hydroxyl (OH) groups, one on each terminal ring. These can be "free" (unreacted) hydroxyls, or can react with an acid (such as a fatty acid) to form an ester. If one hydroxyl reacts with a fatty acid, the result is termed a mono-ester. If both hydroxyl groups are reacted with fatty acids, the result is termed a di-ester. Adding a fatty acid to form an ester makes the esterified end of the molecule more hydrophobic. In order of hydrophobicity (difficulty in dissolving in water), we find that di-esters > mono-esters > free.

In summary then, astaxanthin occurs in several different forms which can be classified according to stereoisomers, geometric isomers, and free or esterified forms. All of these forms are found in various natural sources. For example, the predominant stereoisomer of astaxanthin found in krill (Euphausia superba, a shrimp-like marine animal) is 3R,3'R (Bernhard 1990), and the majority of this is esterified (Foss et al., 1987). In wild salmon, the predominant stereoisomer is 3S,3'S; in salmon flesh the astaxanthin occurs as the free xanthophyll (Bernhard 1990). The basidiomycete yeast Xanthophyllomyces dendrorhous (formerly Phaffia rhodozyma) (Gobulev 1995) accumulates astaxanthin as its major carotenoid; in this yeast, astaxanthin occurs as the 3R,3'R stereoisomer and is predominantly esterified. In the green alga Haematococcus pluvialis, astaxanthin occurs as the 3S,3'S stereoisomer (Bernhard 1990). Astaxanthin from H. pluvialis occurs primarily as monoesters (~80%) and diesters (~15%); the predominant fatty acids that make up the esters are C18:1 and C20:0 (Renstrøm and Liaaen-Jensen 1981).

In one study (Østerlie et al. 1999c), rainbow trout (Oncorhynchus mykiss) were fed a diet containing synthetic non-esterified astaxanthin in a 1:2:1 mixture of the three stereoisomers 3S,3'S, 3R,3'S, and 3R,3'R; one group of fish received predominantly all-E astaxanthin and a second group received an E/Z mixture. The all-E diet resulted in a greater uptake of astaxanthin, indicating that this geometric isomer is more easily digested by trout. In feces, blood, liver, and fillet, the R/S distribution was close to 1:2:1, but in skin and kidney the ratios were about 1:2:2 and 1:2:3, respectively. In rainbow trout, at least, geometric and stereoisomers are distributed selectively in different tissues.

One study on the kinetics of dietary astaxanthin uptake by humans has been reported (Østerlie et al. 1999a, 1999b). In this study, three middle-aged, smoking, male volunteers were given a single olive oil-containing meal with 100 mg of synthetic non-esterified astaxanthin as a defined mixture of all-E (all-trans), 9Z (9-cis), and 13Z (13-cis) geometric isomers (and with the 3S,3'S:3R, 3'S:3S,3'S stereochemical ratio of 1:2:1). The appearance and distribution of astaxanthin was quantified by HPLC analysis of blood samples taken ten times over the 72 hours following the meal. The maximum plasma concentration of astaxanthin was 1.24 mg/L, observed 6 hours postprandially. There was an enrichment of the 13Z isomer in plasma; whether this was due to a preferential uptake of the 13Z isomers, preferential catabolism of the all-E and 9Z isomers, in vivo isomerization, or some other process was not determined. Distribution of the E/Z isomers was consistent among chylomicrons/VLDL, LDL, and HDL lipoprotein fractions. During the absorptive phase, the relative concentration of total astaxanthin in HDL decreased compared to the other lipoprotein fractions. The relative ratio of stereochemical isomers remained unchanged (Østerlie et al.1999b). The results of this one study indicate that geometric isomerism may be important in the bioavailability of free astaxanthin in humans.

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How is synthetic astaxanthin different from natural astaxanthin?

Synthetic astaxanthin is produced as the free (unesterified) xanthophyll and as a 1:2:1 mixture of the three stereoisomers: 3S,3'S, 3R,3'S, and 3R,3'R. The industrial producers of synthetic astaxanthin are Hoffmann-La Roche AG and BASF AG.

Are there different forms of natural astaxanthin?

In its natural state, astaxanthin is usually associated with other molecules (Bernhard, 1990). It is often complexed with proteins, producing an array of colors in different organisms. For example, it is the chromophore in the blue, green, and yellow pigments of lobsters. In other cases, astaxanthin may simply be dissolved in the lipid fraction of complex molecules such as egg lipoproteins, or it may actually be bound chemically to molecules such as fatty acids to form esters. Reddening of some snow algae (Bidigare et al. 1993) and Haematococcus is the result of such esters accumulating in cytoplasmic lipid droplets. Less often, because it is not as stable, astaxanthin occurs in cells as a free, unbound molecule.

Whether free or complexed, the atoms comprising an astaxanthin molecule can be oriented in different ways, producing different isomers. The most common geometric configuration in both synthetic and natural astaxanthin is the most thermodynamically stable all-E (all-trans) isomer. Astaxanthin from natural sources tends to occur predominantly as either the 3S,3'S or 3R,3'R form, while the meso (3R,3'S) isomer is the most abundant in synthetic astaxanthin (Bernhard 1990).

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Why do we think natural astaxanthin may act differently from synthetic astaxanthin?

All-E isomers are the major geometric isomers in both synthetic and natural astaxanthin (Turujman et al. 1997). However, synthetic astaxanthin is produced as free (unesterified) astaxanthin in a mixture of stereoisomers: the stereoisomers (3R,3'R), (3R,3'S) and (3S,3'S) occur in a ratio of 1:2:1. Natural astaxanthin, on the other hand, is usually esterified and predominantly of (3S,3'S) configuration or, less frequently, mainly (3R,3'R) (Bernhard 1990). In Haematococcus pluvialis, astaxanthin occurs as the 3S,3'S stereoisomer and primarily as monoesters (>90%), with diesters comprising ~8% and the free molecule ~1% (Renstrøm et al. 1981). It tends to produce higher pigmentation in rainbow trout compared to synthetic astaxanthin provided at the same dietary concentration (Bowen et al., 1999).

Bidigare, R.R., Ondrusek, M.E., Kennicutt, M.C., II, Iturriaga, R., Harvey, H.R., Hoham, R.W., and Macko, S.A. (1993) Evidence for a photoprotective function for secondary carotenoids of snow algae. J. Phycol., 29: 427-434.

Foss, P., Renstrøm, B., and Liaaen-Jensen, S. (1987) Natural occurrence of enantiomeric and meso astaxanthin. 7. Crustaceans including zooplankton. Comp. Biochem. and Physiol. B, 86B: 313-314.

Renstrøm, B. and Liaaen-Jensen, S. (1981) Fatty acid composition of some esterified carotenols. Comp. Biochem. Physiol. B, 69:625-627.

Østerlie, M., Bjerkeng, B., and Liaaen-Jensen, S. (1999a) On bioavailability and deposition of bent Z-isomers of astaxanthin. Proceedings of the First International Congress on Pigments in Food Technology, Sevilla, Spain, 24-26 March 1999, pp.157-161.

Østerlie, M., Bjerkeng, B., and Liaaen-Jensen, S. (1999b) Blood appearance and distribution of astaxanthin E/Z siomers among plasma lipoproteins in humans administered a single meal with astaxanthin. Abstract 2A-13. Abstracts of the Twelfth International Carotenoid Symposium, Cairns, Australia, 18-23 July 1999, p. 72.

Østerlie, M., Bjerkeng, B., and Liaaen-Jensen, S. (1999c) Accumulation of astaxanthin all-E, 9Z and 13Z geometrical isomers and 3 and 3' RS optical isomers in rainbow trout (Oncorhynchus mykiss) is selective. J. Nutr., 129:391-398.