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Mol. Nutr. Food Res. 61, 6, 2017, 1600469 DOI 10.1002/mnfr.201600469 (1 of 17) 1600469

REVIEW

Canthaxanthin: From molecule to function

Tuba Esatbeyoglu and Gerald Rimbach

Institute of Human Nutrition and Food Science, University of Kiel, Germany

The aim of this review is to summarize the relevant literature about the use of canthaxanthin Received: June 3, 2016
in food science and nutrition research. Canthaxanthin is a red-orange carotenoid that belongs Revised: September 19, 2016
to the xanthophyll group. This naturally occurring pigment is present in bacteria, algae and Accepted: September 20, 2016
some fungi. Canthaxanthin is also responsible for the color of flamingo feathers, koi carp
skin and crustacean shells. Canthaxanthin is widely used in poultry (broiler, laying hens) as a
feed additive. Canthaxanthin can be obtained by total synthesis. The canthaxanthin-mediated
color of foods is an important quality criterion for consumers. Recently, the potential health-
promoting effects of canthaxanthin have been discussed. Canthaxanthin enrichment of LDL
has the potential to protect cholesterol from oxidation. In addition to its free radical scavenging
and antioxidant properties (e.g., the induction of catalase and superoxide dismutase), canthax-
anthin’s immunomodulatory activity (e.g., enhancing the proliferation and function of immune
competent cells) and its important role in gap junction communication (e.g., induction of the
transmembrane protein connexin 43) have been reported. Many studies regarding the poten-
tial health benefits of canthaxanthin have been conducted in vitro and should be validated in
appropriate in vivo models.

Keywords:
Carotenoid / Food colorant / Health benefits / Synthesis / Xanthophyll

1 Chemistry and synthesis
1.1 Chemistry and degradation products of
canthaxanthin
Canthaxanthin (ß,ß-carotene-4,4´-dione; CAS 514-78-3;
C40 H52 O2 ; molecular weight of 564.86 g/mol; Table 1) is
a diketo-carotenoid (4,4´-oxo-carotenoid) with nine con-
jugated C = C-bonds at the center of the molecule [1, 2].
Correspondence: Dr. Tuba Esatbeyoglu
E-mail: esatbeyoglu@foodsci.uni-kiel.de
Abbreviations: ADI, Acceptable Daily Intake; BHT, butylated
hydroxytoluene; CD36, cluster determinant 36; CRTL-b, ␤-ring
hydroxylase; CRTL-e, ␧-ring hydroxylase; CRTW, ␤-carotene ke-
tolase; CRTZ, ␤-ring hydroxylase; DMAPP, dimethylallyl diphos-
phate; EFSA, European Food Safety Authority; FDA, Food
and Drug Administration; GGPP, geranylgeranyl pyrophosphate;
HDL, High Density Lipoprotein; HMBPP, 1-hydroxy-2-methyl-
2-(E)-butenyl 4-phosphate; IDS, IPP/DMAPP synthase; IL-1,
interleukin-1; IL-6, interleukin-6; IPP, isopentenyl diphosphate;
LCY-e, lycopene-␧-cyclase; LCY-b, lycopene-␤-cyclase; LDL, Low
Density Lipoprotein; LPS, lipopolysaccharide; NOAEL, No Ad-
verse Effect Level; RNS, reactive nitrogen species; ROS, Reactive
oxygen species; SR-BI, scavenger receptor class B type I; TEAC,
trolox equivalent antioxidant capacity; TNF-␣, tumor necrosis fac-
tor alpha; VLDL, Very Low density Lipoprotein.
In Fig. 1A, the chemical structures of all-E canthaxanthin
and its geometrical 9-Z and 9,9´-di-Z isomers are shown
as examples. The keto-groups are substituted at the 4-
and 4´-positions of the two ␤-ionone backbones. Because
of the absorption of light in the visible region of the
electromagnetic spectrum at approximately ␭ 470 nm,
depending on the solvent (acetone ␭ 477 nm, petroleum
ether ␭ 466 nm), canthaxanthin appears as a red-orange
lipophilic pigment [3, 4]. The conjugated C = C-bonds,
which act as light-absorbing chromophores, are responsible
for the red-orange color [4–6]. The hue and the color intensity
are also dependent on the chemical structure (the length
of the polyene chain and the number and position of
C = C bonds) [4, 5, 7]. A representative HPLC-chromatogram
and UV-visible absorption spectra (␭ 200 to 650 nm) of
canthaxanthin in acetonitrile:methanol (92.5:7.5, v/v) are
shown in Fig. 2. Because of its nonpolar polyene chain, can-
thaxanthin is insoluble in polar solvents, such as water and
ethanol [8], but it is soluble in tetrahydrofuran [9]. Recently,
Qian et al. (2009) studied the solubility of canthaxanthin
in pure methanol, ethanol, acetone, ethyl acetate, toluene,
cyclohexane, 1,2-dichloroethane, and trichloromethane at
different temperatures from 293.15 to 343.15 K [10]. The
solubility of canthaxanthin improved with increasing tem-
perature. Canthaxanthin is soluble in 1,2-dichloroethane and
trichloromethane [10].


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Table 1. Data sheet: canthaxanthin [2, 8, 141, 142]

Chemical names Canthaxanthin

␤-␤-Carotene-4,4´-dione
4,4´-Dioxo-ß-carotene
Synonyms CI Food Orange 8
INS No. 161 g
CI (1975) No 40850
C.A.S. number 514-78-3
Molecular formula C40 H52 O2
Molecular weight 564.86 g/mol
Melting point 217⬚C (decomposition)
Boiling point 716.95⬚C at 760 mmHg (predicted)
Density 1 g/cm3 (predicted)
Color Deep violet crystals or crystalline powder
Sensitivity To heat, light and oxygen
Storage temperature 2-8⬚C
Application Colorant (in feed, food, drugs, and cosmetics)
Solubility Insoluble in water and ethanol, practically insoluble in vegetable oils, very slightly
soluble in acetone and methanol, and soluble in chloroform and oil
log P (n-octanol-water) 8.71 or 9.79
Absorption maxima Between 468 and 472 nm in cyclohexane
Acute toxicity LD50 10,000 mg/kg (oral; mouse)

The oxidation products of canthaxanthin in vitro following
a treatment with oxygen have recently been identified [11].
The oxidation profile of canthaxanthin could be similar to
that of ␤-carotene. For canthaxanthin, 4-oxo-␤-apo-carotenals
and 4-oxo-␤-apo-carotenones were primarily obtained as oxi-
dation products [11]. In addition, some 5,6-epoxy compounds
are created [11]. The chemical structures of some of the iden-
tified oxidation products of canthaxanthin are depicted in
Fig. 3. Moreover, the degradation of carotenoids with carbonyl
groups (canthaxanthin and astaxanthin) by acid is slower than
that of ␤-carotene and zeaxanthin [12]. Carotenoids, includ-
ing canthaxanthin, usually occur in their all-E isomers, but Z-
isomers are formed during the thermal processing of food [13,
14], and they possess other biological effects and are thermo-
dynamically less stable than E-isomers [15]. Z-Canthaxanthin
has a hypsochromic shift of approximately ␭ 8 nm and an
additional absorption maximum at ␭ 363 nm [16].
1.2 Synthesis of canthaxanthin
From over 700 carotenoids, only 10 are marketed commer-
cially [17]. The global carotenoid market was estimated to be
$1.5 billion in 2014 and an annual growth rate of 3.9% until
2019 is expected [18]. In 2014, astaxanthin reached the high-
est global market value, followed by ␤-carotene [17]. Canthax-
anthin is naturally occurring and can be obtained via total
synthesis [19] or biosynthesis by microorganisms [20–23].
Moreover, an efficient extraction of canthaxanthin from
Escherichia coli has been described [24].
The synthesis scheme of canthaxanthin is shown in Fig. 4.
6-Oxo-isophorone (C9 -ketosiophorone 1) is a common start-
ing compound for the synthesis of carotenoids with cyclic end
groups, such as canthaxanthin (14) [25]. The epoxidation of
6-oxo-isophorone (1) with H2 O2 in aqueous NaOH solution
yielded 4-hydroxy-6-oxo-isophorone (3) [25]. The reduction of
compound 3 to enolized 1,3-diketone (4) was conducted with
zinc/acetic acid or through electrochemical means [25]. This
compound (4) can also be obtained using different synthesis
strategies see Fig. 4A) [19, 25].
There are two alternatives for synthesizing the C15 -Wittig
salt (11) which is a key compound for the synthesis of can-
thaxanthin [25]. Previously, 2,6,6-trimethyl-2-cyclohexenone
was reacted with C6 -acetylene derivatives to build the C15 -
Wittig salt (11) over compound 7, which primarily yielded the
Z-isomer (10) [19, 26] (Fig. 4B). Therefore, instead of 2,6,6-
trimethyl-2-cyclohexenone and an E-enyne, compound 5 was
used to address this challenge [19]. At first, compound 4 re-
acted with isobutyl alcohol to form isobutyl ether (enol ether 5)
[19]. The lithium salt (6), which is the most suitable acetylide
for this reaction, can react with the hindered keto group of
5 [25]. The condensation of compound 5 with 6 followed by
acid hydrolysis yielded compound 7 (90% yield) [19]. In addi-
tion, acetylenic C15 -hydroxy-ketone (7) can react with a Wittig
reagent to form compound 8 [25]. The hydrogenation of the
triple bond of compound 7 or the reduction of the triple bond
with zinc/acetic acid leads to the formation of 7Z-C15 -alcohol
(10), which was yielded after treatment with PB3 (phosphorus
tribromide) and Wittig reagent PPh3 (triphenyl phosphonium
ylide) the desired all-E-C15 -Wittig salt (11) (90% E and 10%
Z) [19, 25].
The reaction of two equivalents of the C15 -phosphonium
salt (11) with the symmetrical C10 -dialdehyde (12) as the
central building block over the double Wittig olefination
(C15 +C10 +C15 = C40 ) in ethanol (with butylene oxide as HX
acceptor) leads to the synthesis of Z/E-canthaxanthin (13;
Fig. 4C) [19, 25]. In addition to the desired all-E-configured
carotenoids, mono-(Z)- and di-(Z)-stereoisomers are also


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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
formed [27]. The poorly soluble all-E-canthaxanthin crystal-
lized out (14; 80% yield) [19, 25] and can be removed easily
from the undesired Z-isomers [27].
A major disadvantage of Wittig olefination is the forma-
tion of triphenylphosphine oxide, which is difficult to sep-
arate and can be circumvented by sulfone compounds [28].
The major advantage of so-called sulfone chemistry is that
the intermediate sulfone compounds are stable over a long
period and can simply be purified by recrystallization [29].
In 2005, Choi and Koo described an efficient synthetic route
for canthaxanthin (14) via the oxidation of C40 -trisulfone (17)
[29]. The synthesis of canthaxanthin is depicted in Fig. 5.
Compound 17 was produced by the coupling reaction of two
equivalents of C15 -allylic sulfone (15) with one equivalent of
C10 -bischloroallylic sulfone (16; 85% yield). Compound 17
precipitated with HCl and was purified by recrystallization.
The iodine-catalyzed allylic oxidation in the cyclohexene ring
of C40 -trisulfone (17) yielded oxidized C40 -trisulfone (18; 82%
yield). After the Ramberg-Bäcklund reaction of compound
18 using a mild base, NaOMe was produced in the pres-
ence of CCl4 , C40 -disulfone (19) with a yield of 73%. The
base-promoted dehydrosulfonation (NaOEt in EtOH) of com-
pound 19 provided E-canthaxanthin (14) at a sufficient yield
(86%).

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Figure 1. (A) Chemical struc-
tures of all-E canthaxanthin and
its possible geometric isomers
(i.e. 9-Z and 9,9´-di-Z) and (B)
chemical structure of all-E 4-oxo
retinoic acid.
2 Occurrence, biosynthesis, and dietary
sources
Carotenoids are synthesized by photosynthetic plants, bac-
teria, algae, and some fungi [30, 31]. The edible mushroom
Cantharellus cinnabarinus contains canthaxanthin; canthax-
anthin was isolated for the first time from this mushroom
[32]. The potential algal sources of canthaxanthin are the
green alga Haematococcus pluvialis [33] and the microalgae
Chlorella zofingiensis [34] and Dactylococcus dissociatus MT1
[35], among others. Furthermore, the gram-negative bac-
terium Paracoccus sp. and the gram-positive bacterium Di-
etzia sp. produce canthaxanthin [22, 23, 36]. The biosynthe-
sis of carotenoids has been described in several studies
[7,20,22,23]. In Fig. 6, a schematic diagram of the biosynthetic
pathway of some carotenoids, including canthaxanthin, is
shown. The precursors for carotenoid biosynthesis are pyru-
vate and D-glyceraldehyde-3-phosphate [7]. Over several steps,
the C5 -compounds dimethylallyl diphosphate (DMAPP) and
isopentenyl diphosphate (IPP) are built from 1-hydroxy-
2-methyl-2-(E)-butenyl 4-phosphate (HMBPP) with the en-
zyme IPP/DMAPP synthase (IDS) in a 1:5 ratio [7]. Chain
elongation was achieved via several head-to-tail condensa-
tion steps of the C5 -compounds. Finally, two equivalents of
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40
A 36
32

E-canthaxanthin
28
Response [mV]

24
20
16
12
8
4
0
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0
RT [min]

B 40 474 nm Time = 3.07 min

36
32
Response [mV]

28
24
20
16
12
8
4
0
200 250 300 350 400 450 500 550 600 650
Wavelength [nm]

Figure 2. (A) A representative HPLC-chromatogram of E-canthaxanthin standard purchased from Sigma (Steinheim, Germany; 5 ␮M)
dissolved in acetonitrile:ethanol (92.5:7.5, v/v; containing 37.5 mg/L ascorbic acid and 37.5 mg/L BHT) at ␭ 475 nm. The HPLC conditions

were as follows: the separation was performed using a reversed-phase column (Kinetex 2.6 ␮m C18 100 Å, 100 × 4.6 mm; Phenomenex,
R

Aschaffenburg, Germany) with a guard column. Acetonitrile:methanol (92.5:7.5, v/v; isocratic elution) was used as the mobile phase. The
flow rate was set at 1.0 mL/min and the column oven temperature was set at 25⬚C. The injection volume was 20 ␮L. (B) UV-visible absorption
spectra of canthaxanthin (5 ␮M) dissolved in acetonitrile:ethanol (92.5:7.5, v/v; containing 37.5 mg/L ascorbic acid and 37.5 mg/L BHT) from
␭ 200 to 650 nm.

geranylgeranyl pyrophosphate (GGPP; C20 ), which are
derived from four C5 -units, condensed head-to-head
and result in 15-Z-phytoene (C40 ) formation [7]. Sev-
eral desaturation steps introduce conjugated C = C
bonds into phytoene (colorless) and yield all-E-lycopene
(red-colored) after isomerization [7]. Two major cy-
clase enzymes known as lycopene-␧-cyclase (LCY-e)
and lycopene-␤-cyclase (LCY-b) catalyze the formation of
cyclic end groups (␣- and ␤-ionone backbones) from the
acyclic precursor all-E-lycopene [7]. In this way, ␣-carotene
and ␤-carotene are formed. Xanthophylls are the oxidation
products of ␣- and ␤-carotene. The introduction of hydroxyl
moieties into the cyclic ring at 3,3´-positions of ␣-carotene and
␤-carotene is catalyzed by hydroxylases (CRTL-b and CRTL-e).
This enzyme-catalyzed reaction yields lutein and zeaxanthin
via ␣-cryptoxanthin and ␤-cryptoxanthin, respectively [7]. The
conversion of ␤-carotene into canthaxanthin over echinenone
is performed by the ␤-carotene ketolase enzyme (CRTW)
[20, 23]. This enzyme introduces the keto groups at the 4,4´-
position to ␤-rings.
Animals and humans are not able to biosynthesize can-
thaxanthin or any other carotenoids, and so they ingest these
compounds from dietary sources [30, 37]. In many animals,
a red-orange color is derived from the diet. Birds may eat
feed that is rich in carotenoids, i.e., maize, algae, shrimp,
mollusks, and insect larvae. Marine animals such as crus-
taceans primarily consume algae, and the food source of wild
fish is often composed of plankton and small crustaceans,
which may contain carotenoids [30, 38, 39]. The red-orange
pigment canthaxanthin occurs in red-feathered birds such
as flamingos (Phoenicopterus chilensis, Phoenicopterus ruber,
and Phoenicopterus roseus), the scarlet ibis (Eudocimus ruber),
the summer tanager (Piranga rubra), the white-browed pur-
pletuft (Iodopleura isabellae) [3, 30, 31, 40], cardinals, robins
and orioles [41] and in fish such as carp (Cyprinus carpio),
golden mullet (Mugil auratus), seabream (Diplodus annularis)
and thrush wrasse (Crenilabrus tinca) [30, 42, 43]. The red-to-
pink color of salmonids is mediated by the ability to combine
canthaxanthin with actomyosinic acid complexes in muscle
[44].
The freshness and color of animal foods are important
buying criteria for consumers, and these traits are associated
with high-quality foods and healthy products. Therefore,
carotenoids, including canthaxanthin, are added to animal
feed to color foods (egg yolks, broilers, salmon, and trout)
and to satisfy consumer expectations [45]. Canthaxanthin
is present in, i.e., poultry, egg yolks, farmed trout, and
salmon (Salmo salar L.) because of its application as a feed


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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
Figure 3. Possible in vitro oxidation products of canthaxanthin (according to [11]).
additive (E 161g) [43]. However, the binding of actomyosin to
canthaxanthin is not specific [46]. As a lipophilic compound,
canthaxanthin accumulates in food, mostly in fatty tissues,
i.e., broiler skin, egg yolks, and fish fillets, and in the cuticles
of crustaceans [38].
Dietary canthaxanthin supplementation in a breeder’s
diet significantly increased the anti-oxidative status of egg
yolks, and the hatching rate of chicken eggs was signifi-
cantly increased [47]. It seems that canthaxanthin has a ben-
eficial effect on early postnatal development [47]. Moreover,
carotenoids have a positive effect on animal health and prod-
uct quality [38].
The occurrence of canthaxanthin in flamingos, koi carp,
salmon, egg yolks, chanterelles, and crustaceans is depicted
in Fig. 7.
3 Absorption, bioavailability, and tissue
distribution
The number of publications concerning canthaxanthin
bioavailability is rather limited. Carotenoids from raw veg-
etables, i.e., spinach, carrot, and peppers, are relatively low
in bioavailability, but carotenoids from papaya, melon, and
sweet potatoes, for example, show moderate bioavailabil-
ity [48], whereas fat and lipid-based formulations may im-
prove the bioavailability of carotenoids, including canthax-
anthin [31, 48, 49]. Adding oil to food during cooking has
been shown to raise the bioavailability of carotenoids to
a noteworthy extent [50–53]. Approximately 3–5 g fat per
meal is recommended for optimal carotenoid absorption [54].

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In addition, thermal, mechanical and enzymatic treatment
improve bioavailability, likely by dissociation or through the
weakening of the protein-carotenoid complex and the dis-
ruption of the matrix (cell wall structure) [48, 50, 55, 56].
Carotenoids from vegetables are less bioavailable than those
from fruits [57]. Furthermore, Schweiggert and Carle (2015)
stated high carotenoid bioavailability from animal-derived
food [58]. Overall, the bioavailability of carotenoids is influ-
enced by the dietary source (food or supplement), degree
of processing, interactions with other carotenoids, degree of
isomerization, transit time in the intestine, nutritional status,
age, gender and genetic makeup [50, 59–61].
Carotenoids are absorbed along with dietary lipids through
passive diffusion or by scavenger receptors, such as scavenger
receptor class B type I (SR-BI) and cluster determinant 36
(CD36), for mediated uptake into the enterocytes [55, 62, 63].
The absorption of carotenoids has many parallels to that of
lipids [55, 59]. For their absorption, carotenoids must be re-
leased from the food matrix [59, 64, 65]. The carotenoids are
then incorporated into mixed micelles, which consist primar-
ily of free fatty acids, bile salts, cholesterol, phospholipids, and
other lipids [59, 62]. Together with lipids, bile salts emulsify
the carotenoids [50]. These mixed micelles may “dock” to the
enterocytes and carotenoids will then be absorbed by passive
diffusion or transporters [66]. Carotenoids are incorporated
into chylomicrons (triglyceride-rich lipoproteins), and they
migrate to the lymphatic system [62, 66]. Carotenoids are re-
leased into the systemic circulation and are then distributed
to the different peripheral tissues [62]. Lipoproteins are pri-
marily responsible for carotenoid distribution to peripheral
tissues. More polar carotenoids, such as canthaxanthin are
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Figure 4. Synthesis scheme of can-

thaxanthin according to Rosen-
berger et al. (1982), Widmer (1985)
and Ernst (2002) [19,25,27]. Prepara-
tion of enolized 1,3-diketone (4; A),
all-E-C15 -Wittig salt (11; B) and all-E-
canthaxanthin (14; C).


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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
Figure 5. Synthesis scheme of canthaxanthin via C40 -trisulfone
(17) according to Coi and Koo (2005) [29].
carried by LDL (low density lipoprotein) and HDL (high
density lipoprotein) particles [55, 59]. Generally, lipophilic
carotenoids are found in the lipid domains of tissues such
as liver and skin [59]. The highest canthaxanthin concentra-
tions were in the liver and also in the fat, lungs and small
intestines of ferrets [67]. Experimental data suggest the in-
duction of cytochrome P4501A1 and 1A2 by canthaxanthin
[68, 69].
Non-polar carotenoids, i.e., ␤-carotene, remain in the in-
ner part of the lipid membrane. The polar groups of polar
carotenoids, i.e., canthaxanthin, interact with the polar heads
of the membrane [5]. The localization of canthaxanthin in
lipid membranes and its interaction with lipid molecules
seem to play an important role in many of the biological
functions of canthaxanthin [70, 71]. It is suggested that can-
thaxanthin that has been incorporated into lipid membranes
is distributed between two pools, with one spanning the bi-
layer almost perpendicularly to the surface and one lying
parallel to the membrane. Furthermore, it is suggested that
the horizontal fraction of canthaxanthin increases with the
concentration of the pigment [70].

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After the consumption of single 75 mg or 150 mg doses
of canthaxanthin in capsules with milk cream, the absorption
rate of canthaxanthin was 9–12% of the administered dose
[43]. In another study, volunteers received 30 mg or 96 mg
canthaxanthin in capsules with milk cream over 5 (6 times
a day at 1 mg of canthaxanthin) or 2 days (6 times a day at
8 mg of canthaxanthin), respectively. The plasma concentra-
tions of canthaxanthin were 3.2 or 18.2 ␮mol/L, respectively,
after daily intake (6 or 48 mg ingested, respectively). The max-
imum plasma concentrations were detected after 48 h [43].
The fraction of the dose absorbed was a max. of 34%. Ap-
proximately 60% of the absorbed dose was accumulated in
fat tissue [43]. In a third study, human volunteers consumed
150 mg or 75 mg canthaxanthin in a single dose. The ab-
sorption rate of canthaxanthin ranged from 8 to 15% [43]. In
plasma, 48% of canthaxanthin was associated with lipopro-
teins, and 52% of canthaxanthin was transferred to the fat
tissues [43]. The elimination half-life of canthaxanthin from
serum was approximately 5 days, and maximum serum con-
centrations (cmax ) were achieved after 48 h [43].
The bioavailability of canthaxanthin may be affected by
other antioxidants, partly because of their interactions during
intestinal absorption [72]. White and co-workers (1994) sug-
gested that a combined pharmacological dose of ␤-carotene
and canthaxanthin significantly decreases the bioavailabil-
ity of canthaxanthin in humans [73]. Accordingly, Paetau
et al. (1997) found that the ingestion of a combined dose of
␤-carotene and canthaxanthin reduced the appearance of can-
thaxanthin in plasma, chylomicrones and VLDL (very low
density lipoprotein) [74]. Furthermore, excess of vitamin E de-
creased canthaxanthin absorption in rats [75]. Vitamin E and
carotenoids may follow similar absorptive pathways, thereby
influencing their absorption. In addition, canthaxanthin in-
hibits lycopene uptake [72].
The metabolism of canthaxanthin and its tissue distri-
bution in humans is nearly unknown. In humans, only a
limited number of carotenoid metabolites and degradation
products, primarily epoxides and apo- or seco-carotenoids,
have been described or suggested [63,76]. In comparison with
humans, rats, and fish seem to exhibit different metabolic
pathways for canthaxanthin. 3-Hydroxy-4-oxo-7,8-dihydro-␤-
ionone was identified as a major canthaxanthin metabolite
in the urine of rats [77]. In poultry livers, canthaxanthin
was reduced to 4-hydroxyechinenone (4-hydroxy-4´-keto-␤,␤-
carotene), and this compound was converted in part to
isozeaxanthin (4,4´-dihydroxy-␤,␤-carotene) [78].
4 Safety
Carotenoids, including canthaxanthin, have been evaluated
by the European Food Safety Authority (EFSA) in Europe and
the Food and Drug Administration (FDA) in the USA for
their safety as food and feed additives [43, 79]. The JECFA
(Joint Expert FAO/WHO Committee on Food Additives) and
SCF (Scientific Committee on Food) have defined an ADI
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1600469 (8 of 17) T. Esatbeyoglu and G. Rimbach
Figure 6. Simplified biosynthetic pathway of some carotenoids [7, 22]. DMAPP, dimethylallyl diphosphate; IDS, IPP/DMAPP synthase;
IPP, isopentenyl diphosphate; IPPi, IPP isomerase; LCY, lycopene cyclase; CRTL-b, ␤-ring hydroxylase; CRTL-e, ␧-ring hydroxylase; CRTW,
4,4´-ketolase; and CRTZ, 3,3´-hydroxylase.
(Acceptable Daily Intake) for canthaxanthin of 0.03 mg/kg
bw that was derived from the NOAEL (No Adverse Effect
Level) [30, 43]. The oral LD50 of canthaxanthin in mice is
10,000 mg/kg bw [43]. In addition to its low acute oral toxic-
ity, canthaxanthin is not genotoxic [43]. Consequently, dietary
canthaxanthin is considered to be safe for humans.
In poultry, the liver is the target tissue of canthaxanthin
deposition in addition to skin/fat and egg yolks; this depo-
sition is directly proportional to the dietary canthaxanthin
intake, and it occurs in fish (salmon, trout) skin and flesh
[80]. The consumption of canthaxanthin that is derived from
egg yolks, poultry and fish does not normally exceed the ADI
levels [80]. The maximum canthaxanthin residue levels are

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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
proposed for the following foods to ensure consumer safety:
30 mg/kg for egg yolk, 15 mg/kg for poultry liver, 2.5 mg/kg
for poultry skin/fat, 10 mg/kg for salmon and 5 mg/kg trout
flesh [80–82]. The estimated intakes of canthaxanthin based
on French (application as food additive) and Irish (application
as feed additive) populations have averages of 9.6 ␮g/kg bw
for children (95th percentile: 23.6 ␮g/kg) and 6.1 ␮g/kg bw
for adults (95th percentile: 16.1 ␮g/kg) [43]. These values do
not exceed the ADI level. The egg is the primary contributor,
providing 70–80% of human canthaxanthin exposure [43].
In fish feed, canthaxanthin has been replaced almost com-
pletely by the carotenoid astaxanthin for trout and salmon
applications because of a lower pigmenting efficacy [83].
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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
Figure 7. Occurrence of canthaxanthin: (A) flamingo (Phoeni-
copterus sp.; Copyright: Erlebnis Zoo-Hannover), (B) koi carp
(Cyprinus carpio “Showa” or “Tancho Sanke”; Copyright: Koi-
Zentrum-Todtenbier), (C) farmed salmon flesh (Salmo salar L.;
Norway), (D) egg yolks, (E) chanterelle edible fungus Cantharel-
lus cibarius, and (F) crustaceans.
The potential toxic effects of canthaxanthin in humans
are ocular lesions mediated by macular crystal formation and
retinopathy [44, 84, 85]. On a molecular level, the formation
of canthaxanthin aggregates could be caused by hydrogen
bonds between canthaxanthin keto groups and the C = O
group of the lipid or hydrogen bonds between the polyene
chain and water [86]. Canthaxanthin ocular toxicity is primarly
related to the consumption of unsafe sun-tanning pills [87],
which exceed the dietary intake of canthaxanthin from eggs,
poultry, and fish. These tanning pills contain up to 30 mg
of canthaxanthin [88]. The cessation of canthaxanthin intake
or topical application reverses retinopathy with a very good
prognosis, but with interindividual variations [89]. However,
canthaxanthin causes no long-term adverse effects [85].
5 Food coloring and pigmentation and its
regulation
Synthetic canthaxanthin is a nature-identical compound [90].
Canthaxanthin gives animal-derived food its characteristic
red-orange hue [3]. The size, shape, or conformation of
carotenoids also play key roles in their coloring properties
[40]. The polyene chain of canthaxanthin is responsible for
its instability against oxidation [1]. In addition, carotenoid-
protein interactions are responsible for a wide range of “red”
colors, i.e., in plumage samples [40]. The typical red color

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(9 of 17) 1600469
of shrimp and other crustaceans [38] appears via the heat-
induced denaturation of carotenoproteins [91].
During the oxidation and degradation of carotenoids, the
color intensity decreases or can be lost. Therefore, the stabi-
lization of carotenoids in, i.e., feed products, is necessary. The
stabilization of chemically synthesized carotenoids to avoid
oxidative processes and degradation is achieved by adding
antioxidants (i.e., butylated hydroxytoluene (BHT) or toco-
pherols), forming beadlets (containing antioxidants) or coat-
ing [30, 38]. Therefore, carotenoids, including canthaxanthin,
are mostly available at 10% concentrations in edible oils or
fats, emulsions, cold water-dispersible powders or beadlets
(Ø 0.4 mm) [43, 90]. These water-soluble beadlets contain
water-dispersible canthaxanthin (10%) in combination with
gelatin, sucrose, peanut oil, or ascorbyl palmitate as emul-
sifiers and dl-␣-tocopherol as an antioxidant. The surface is
covered with cornstarch [43].
In Table 2, the maximum permitted levels of the col-
orant canthaxanthin in animal-derived food and feed stuff
are given. According to “Regulation (EC) No 94/36”, annex
IV (colors permitted for certain uses only), canthaxanthin
(E 161g) is permitted for use as a food additive for color-
ing Strasbourg sausages (Saucisses de Strasbourg; 15 mg/kg)
[92], but sausage producers stopped using it years ago.
The use of additives in animal nutrition is determined by
“Regulation (EC) No 1831/2003” [93]. Colorants for coloring
the feedstuff (i) and consequently coloring animal-derived
foods (ii) and affecting the color of ornamental fish or birds
(iii) are dedicated to the “sensory additives” category (annex
I No 2a) [93]. Based on “Regulation (EC) No 1831/2003,” the
“Register of Feed Additives” lists canthaxanthin as a “sensory
additive” (functional groups ii and iii) under “carotenoids and
xanthophylls,” which may be used as a feed additive to add
color to feed and to color food of animal origin [94]. The
“Commission Directive No 2003/7” [95] and the “Commis-
sion Implementing Regulation (EU) 2015/1486” [82] autho-
rizes canthaxanthin as a feed additive for salmon and trout
[95], poultry, including laying hens [82, 95], and ornamental
fish and birds, including ornamental breeder hens [82]. To en-
sure consumer safety, it is permissible to use up to 25 mg can-
thaxanthin/kg in salmonid feed (e.g., salmon and trout aged
up to 6 months) and poultry (other than laying hens) feed and
8 mg/kg for laying hen complete feed [82, 95]. Currently, the
following mixture of canthaxanthin with other carotenoids
and xanthophylls is permitted: up to 80 mg/kg in complete
feed for poultry (canthaxanthin with other carotenoids and
xanthophylls) and 100 mg/kg (canthaxanthin with astaxan-
thin) in feed for 6-month-old salmon and trout [30, 82, 95].
The use of canthaxanthin as a feed additive for breeder hens
is also regulated by the “Commission Implementing Regu-
lation (EU) No 684/2014” (6 mg/kg of complete feed stuff)
[96]. In ornamental fish and ornamental birds (except or-
namental breeder hens: 8 mg/kg), a max. of 100 mg can-
thaxanthin/kg of complete feed stuff is permitted [82]. In
flamingos, canthaxanthin is important for the color and
brightness of feathers, and in koi carp, it improves skin
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1600469 (10 of 17) T. Esatbeyoglu and G. Rimbach
Table 2. Maximum permitted levels of the colorant canthaxanthin in animal-derived food and feed stuff
Food or feed stuff
Saucisses de Strasbourg
Feed stuff for poultry other than laying hens, salmon, and trout
Feed stuff for laying hens
Feed stuff for breeder hens
Feed stuff for ornamental fish and ornamental birds
Feed stuff for ornamental breeder hens
pigmentation. According to “Commission Regulation (EC)
No 880/2004”, canthaxanthin is also allowed for use as a feed
additive in pet and ornamental bird feed without a time limit
[97]. In compliance with “Commission Regulation (EC) No
1288/2004”, astaxanthin-rich Phaffia rhodozyma is permitted
for feeding salmon and trout from the age of 6 months on-
wards at a max. of 100 mg/kg (expressed as astaxanthin)
complete feed stuff [98]. Mixture with canthaxanthin is also
allowed, but the total concentration of astaxanthin and can-
thaxanthin must not exceed 100 mg/kg in the complete feed
stuff [98].
Consumers associate a certain quality standard with the
color of food [99]. Therefore, the addition of carotenoids to
fish feed to improve the color of the flesh of farmed salmon, to
laying hen diets to color the egg yolks and to chicken diets to
color skin pigmentation are well-known procedures [30, 90].
Thus, canthaxanthin is used in feedstuffs for laying hens for
the coloring of egg yolks, in poultry for coloring the skin, in
salmon and trout farming for coloring the flesh [3], and also
for dogs, cats, ornamental fish, and birds [30, 38].
The color of salmonids varies from pale, weak red to deep
red. Depending on the size of the fish, canthaxanthin is per-
mitted in salmonid feed at concentrations of up to 80 mg/kg
[30]. To obtain a similar strong color in farmed salmon to
that of wild salmon, astaxanthin alone or with canthaxan-
thin is added to fish feed [100]. Fish flesh has been found
to contain approximately 8 mg/kg canthaxanthin [101]. In
rainbow trout, higher amounts of canthaxanthin in the flesh
were detected than in Atlantic salmon and sea trout [102].
Canthaxanthin reached concentrations of up to 20–25 mg/kg
in rainbow trout [103].
The carotenoids lutein (E 161b), capsanthin (E 160c), zeax-
anthin (E 161h), canthaxanthin (E 161g), ␤-apo-8´-carotenal
(E 160e), ethyl-8´-apo-␤-carotene-8´-oate (E 160f), citranaxan-
thin (E 161i) and ␤-cryptoxanthin (E 161c) are registered
as additives in poultry feed [104]. In addition to canthax-
anthin, the carotenoids lutein, zeaxanthin, canthaxanthin,
ß-carotene and ß-apocarotenoic ester are mostly present in
eggs [105, 106], and they make an important contribution to
the wide hue range (yellow to red) in egg yolks. Egg yolks
under organic farming owe their color to feed such as al-
falfa (Medicago sativa) or corn (Zea mays), which contain
lutein, zeaxanthin and in smaller amounts ␤-cryptoxanthin
[45,104]. The color of egg yolk is proportional to the carotenoid
concentration in the diet of laying hens. By using the Yolk

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Maximum level of canthaxanthin Reference
15 mg/kg [92]
25 mg/kg [82, 95]
8 mg/kg [82, 95]
8 mg/kg [96]
100 mg/kg [82]
8 mg/kg [82]
Colour Fan, the color intensity can be classified on a scale
from 1 (pale yellow) to 15 (reddish orange) [30]. Since 2001,

R
the Yolk Fan has been used, and it is equivalent to the
old Roche Fan. Egg yolk marketed in Germany, for exam-
ple, has a visual color score of 11-14 (RYCF), which cor-
responds to a canthaxanthin content of 0.13-0.35 mg/egg
[30]. The lowest RYCF score (7-9) is shown for eggs from
the Netherlands [30]. In boiled eggs, the RYCF score is 1-
2 units lower than it is in fresh eggs [30]. A maximum of
5.9 mg canthaxanthin/kg egg was detected, if the feed con-
tained up to 80 mg/kg canthaxanthin [30]. The lowest canthax-
anthin level was described for broiler skin/fat (2.5 mg/kg) and
broiler meat (0.23 mg/kg) [30].
6 Potential health benefits
During the past two decades, several potential health ben-
efits of canthaxanthin have been discussed. Canthaxanthin
exhibits free radical scavenging properties. Furthermore,
immune-modulating activities and an induction of gap junc-
tion communication from canthaxanthin have been sug-
gested.
6.1 Free radical scavenging and antioxidant
properties
Reactive oxygen species (ROS), such as superoxide, hydroxy
and peroxy radicals, singlet oxygen and hydrogen perox-
ide and reactive nitrogen species (RNS), e.g., peroxynitrite
(ONOO− ) [107], may generate oxidative and nitrosative dam-
age to DNA, lipids, and proteins [108].
Xanthophylls, particularly keto-carotenoids, such as asta-
xanthin and canthaxanthin, were better free radical scav-
engers and antioxidants in vitro than carotene carotenoids,
such as lycopene and ␤-carotene [109]. For this purpose, the
keto group in conjugation with the polyene backbone is re-
sponsible for stabilizing the carbon-centered radicals more
effectively than the polyene backbone alone [109]. Because
of the keto groups, the initial rate of canthaxanthin oxidation
was suggested to be lower than that of lycopene or zeaxanthin
[110].
In general, canthaxanthin scavenges reactive oxygen
species [111], but canthaxanthin does not seem to scavenge
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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
peroxynitrite anion free radicals (ONOO− ) [107]. Geometrical
isomerization seems to have an impact in terms of the free
radical scavenging activity of canthaxanthin [1]. Recently, 9-
Z-canthaxanthin was shown to be more effective than all-E-
canthaxanthin at scavenging superoxide radicals, which may
be related to its higher potential energy [1]. Moreover, can-
thaxanthin is a potent lipophilic antioxidant that quenches
singlet oxygen [112].
In addition to the free radical scavenging and antioxi-
dant properties of canthaxanthin in tube experiments and
cultured cells, canthaxanthin may also exhibit antioxidant
activity in vivo. This activity may positively affect the prod-
uct quality of animal-derived food as well as the health sta-
tus of both humans and animals. In this context, Shih and
co-workers (2008) showed that canthaxanthin supplementa-
tion had modulating effects on lipid peroxidation and an-
tioxidative enzyme activities in rats that were given a high-
cholesterol and high-fat diet. Canthaxanthin significantly de-
creased plasma lipid peroxidation. Both glutathione peroxi-
dase activity in erythrocytes and hepatic superoxide dismutase
activity, which are partly controlled by Nrf2, decreased with
cholesterol feeding, and they were recovered with canthax-
anthin supplementation. These findings suggest that can-
thaxanthin altered the prooxidative/antioxidative balance and
suppressed cholesterol-induced oxidative stress by modulat-
ing endogenous antioxidant defense mechanisms [113]. Ac-
cording to these data in rats, canthaxanthin was also shown
to alter hepatic antioxidant enzymes in mice. Catalase and
superoxide dismutase activities were significantly higher in
canthaxanthin-supplemented mice in comparison with un-
supplemented controls [114]. The same result was observed
in the progeny of hens that were fed with canthaxanthin
[115].
Interestingly, abdominal obesity in women was associ-
ated with oxidative stress as determined by lowered serum
levels of canthaxanthin [116]. Future studies must address
the underlying cellular and molecular mechanisms by which
canthaxanthin and other carotenoids may affect body weight
and body composition.
In cultured neuronal cells, when canthaxanthin was
challenged with hydrogen peroxide or 1-methyl-4-phenyl
pyridinium, canthaxanthin retained significant glutathione
peroxidase and catalase activities, and it decreased lipid perox-
idation (malondialdehyde) and the formation of reactive oxy-
gen species. Furthermore, canthaxanthin significantly sup-
pressed pro-apoptotic caspase-3-activity and the release of the
pro-inflammatory cytokines interleukin-1 (IL-1), interleukin-
6 (IL-6) and tumor necrosis factor alpha (TNF-␣) [117].
The oxidative modification of LDL plays an important
role in the initiation and progression of atherosclerosis [118].
Studies by Linseisen and co-workers (1998) suggest that the
canthaxanthin enrichment of LDL has the potential to pro-
tect cholesterol against oxidation [119]. Similarly, canthaxan-
thin inhibited LDL oxidation by human monocyte-derived
macrophages in vitro in a concentration-dependent man-
ner. Interestingly, canthaxanthin was more effective than

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(11 of 17) 1600469
␤-carotene and zeaxanthin when incorporated into LDL prior
to oxidation [120].
Oxysterols, which are oxidized derivatives of cholesterol,
have been shown to accelerate plaque formation, suggesting
a critical role in atherosclerosis. 7-Keto-cholesterol is a major
cholesterol oxidation product that is found in human athero-
matous plaques [121]. Palozza and co-workers (2008) have
shown that canthaxanthin exerts beneficial effects in vitro on
spontaneous and free-radical-induced cholesterol oxidation,
thereby mediating anti-atherogenic properties [121].
In addition to preventing lipid peroxidation, canthaxan-
thin may also prevent DNA damage. Canthaxanthin de-
creased in vivo aflatoxin B1, DNA single strand breaks and
the binding of aflatoxin B1 to liver DNA. Furthermore, can-
thaxanthin increased the in vitro metabolism of aflatoxin B1
to aflatoxin M1, a less genotoxic aflatoxin metabolite [122].
Sah and co-workers (1995) reported that superoxide anion
free radicals that were generated by the xanthine-xanthine ox-
idase reaction could induce single strand breaks in plasmid
DNA, which was significantly counteracted by canthaxanthin
[123]. Accordingly, canthaxanthin supplementation reduced
the number of micronuclei induced in human cultured lym-
phocytes in vitro by the chemotherapeutic drug bleomycin
[124].
6.2 Immunomodulatory activity
Several studies have suggested the immunomodulatory ac-
tivity of carotenoids [125]. Although the majority of these
studies have focused on the immunomodulatory activity of
␤-carotene, only a few studies have systematically investi-
gated the effect of canthaxanthin on the immune system.
Bendich and Shapiro (1986) were the first to show that di-
etary canthaxanthin significantly increased mitogen-induced
lymphocyte proliferation in rats [126]. Furthermore, Prabhala
and co-workers (1989) observed the enhanced expression of
activation markers in human peripheral blood mononuclear
cells in vitro in response to canthaxanthin treatment [127].
Okai and Higashi-Okai (1996) investigated the possible im-
munomodulatory activities of various carotenoids, including
canthaxanthin, in cultured cells in vitro. The canthaxanthin
treatment of spleen cells and thymocytes that were isolated
from mice resulted in a robust cell proliferative response.
Furthermore, canthaxanthin significantly increased the re-
lease of IL-1 and TNF-␣ in murine peritoneal immune cells.
The authors concluded that carotenoids such as canthaxan-
thin exhibit their immune modulatory activities by enhancing
the proliferation and function of murine immunocompetent
cells [128].
Immunomodulation by carotenoids, including canthax-
anthin, may have the potential to increase host resistance to
pathogens. Furthermore, the activity of canthaxanthin and re-
lated carotenoids to increase gap junction formation may be
mechanistically linked to the inhibition of cell transformation
and early tumor growth [129, 130]. However, canthaxanthin
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1600469 (12 of 17) T. Esatbeyoglu and G. Rimbach
studies in cultured cells in vitro must be verified in appropri-
ate in vivo models in the future.
Interestingly, among other carotenoids, canthaxanthin in-
creased alkaline phosphatase activity in cultured cells [131].
Alkaline phosphatase is centrally involved in the detoxifica-
tion of lipopolysaccharide (LPS) because of its ability to de-
phosphorylate LPS. Thus, because of the induction of alkaline
phosphatase, canthaxanthin may play an important role in an-
tagonizing the detrimental effects of LPS, such as infectious
diseases and chronic inflammation, which warrants further
investigation.
6.3 Gap junction formation
Canthaxanthin is known to enhance gap junction commu-
nication between cells [132]. Recently, the important role of
carotenoids as protective compounds in gastric disorders has
been described as summarized by Vilchez and coworkers
(2011) [90]. Canthaxanthin serves as a chemoprotective agent
against colon carcinogenesis in a rat model [133]. The po-
tential anti-carcinogenic properties of carotenoids may be as-
sociated with their ability to induce gap junction proteins.
Connexin 43, a transmembrane protein, is one of the ma-
jor gap junction proteins in mammalian cells. Gap junc-
tion channels assembled from connexin mediate commu-
nication between adjacent cells because of the exchange
of signaling molecules and ions. Thus, connexins are cen-
tral players in cellular homeostasis, and their dysfunction
may result in chronic degenerative diseases including can-
cer [134]. Hanusch and colleagues (1995) have shown that
4-oxoretinoic acid, a metabolite of canthaxanthin (for chem-
ical structure see Fig. 1B), is an efficient inducer of con-
nexin 43, thereby mediating gap junction formation [132]. In
this context, 4-oxo-retinoic acid is suggested to influence the
stability of connexin 43 mRNA via elements located in the
3´-UTR [135]. Furthermore, it was shown that 4-oxoretinoic
acid binds to the specific nuclear retinoic acid receptor (RAR-
beta) [136], thereby regulating gene expression. The ability of
carotenoids to mediate gap junction communication seems
to be unrelated to their provitamin A and free radical scav-
enging properties regarding the scavenging activity of per-
oxyl free radicals [137]. Accordingly, Stahl and colleagues
(1997) have shown little correlation between the ability of
carotenoids to induce gap junction formation and their sin-
glet oxygen quenching properties [138]. Furthermore, there
was no correlation between gap junction formation and the
so-called trolox equivalent antioxidant capacity (TEAC) of xan-
thophylls as determined by Miller et al. (1996) [139]. Thus,
carotenoids, including canthaxanthin, exhibit important cell
signaling activities that are rather independent of their classi-
cal free radical scavenging and antioxidant properties. Over-
all, the function of canthaxanthin in inducing gap junc-
tional formation may be an important molecular mechanism
that contributes to its ability to inhibit neoplastic formation
[140].

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Mol. Nutr. Food Res. 61, 6, 2017, 1600469
7 Conclusion, outlook, and future
research directions
Collectively, the studies summarized within this review ar-
ticle indicate that dietary canthaxanthin is a safe and widely
used feed colorant in poultry and aquaculture nutrition. Can-
thaxanthin is used as a pigment for the orange/red color of
egg yolks and for salmon and rainbow trout flesh to im-
prove food quality. In contrast to other carotenoids, can-
thaxanthin is not used as a nutraceutical. Beyond its func-
tions as a pigment, the potential health benefits of can-
thaxanthin have also been described, including free rad-
ical scavenging, antioxidant and gene regulatory proper-
ties. However, the molecular targets (e.g., transcription fac-
tors) by which canthaxanthin may mediate the potential
health benefits are largely unknown and warrant further
investigation. There is increasing experimental evidence,
primarily from cultured cells, to suggest that canthaxan-
thin may affect gap junction communication and immune
function.
Only a few studies are available regarding the absorption
and metabolism of canthaxanthin. Unlike other carotenoids
such as ␤-carotene, lycopene and astaxanthin, the biological
functions of canthaxanthin are less studied. Therefore, future
studies should better address the in vivo biological function
of canthaxanthin beyond its colorant properties.
The authors have declared no conflict of interest.
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