Canthaxanthin: From molecule to function.

The aim of this review is to summarize the relevant literature about the use of canthaxanthin in food science and nutrition research. Canthaxanthin is a red-orange carotenoid that belongs to the xanthophyll group. This naturally occurring pigment is present in bacteria, algae and 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), canthaxanthin'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 potential health benefits of canthaxanthin have been conducted in vitro and should be validated in appropriate in vivo models.

A short-term toxicity study of Aspergillus carbonarius carotenoid.

In a pharmacokinetic study, high-performance liquid chromatography analysis of blood samples of Wistar female rats fed with partially saturated canthaxanthin (PSC) of Aspergillus carbonarius showed the presence of the carotenoid in the plasma within 6 hours of feeding. In another study for safety assessment of PSC fed to rats over a period of 28 days at 0.05%, 0.10%, and 0.25%, the rats showed no changes in food intake. There were no significant differences observed in body weight, hematological parameters, or serum clinical enzymes compared to the control group not fed with PSC. Deposition of PSC in the eyes of the rats was also not observed. The results showed that PSC-fed rats were not adversely affected as far as toxicological studies were concerned.

Effect of soybean phospholipids on canthaxanthin lipoproteins transport, digestibility, and deposition in rainbow trout (Oncorhynchus mykiss) muscle.

This study was designed to assess the effect of dietary soybean phospholipids on canthaxanthin transport by serum lipoproteins and canthaxanthin muscle deposition in trout. Three groups of 12 immature trout in triplicate with a mean body weight of 130 g were fed with three experimental diets containing (1) canthaxanthin plus lecithin plus fish oil, (2) canthaxanthin plus lecithin, and (3) canthaxanthin alone, for 12 days. The two major lipoprotein classes in rainbow trout are high-density lipoproteins, which transport principally carotenoids present in the serum, and low-density lipoproteins, which are responsible for the transport of cholesterol, both independently of the administered diet. In addition, very low density lipoproteins are responsible for triglyceride transport in serum. Nevertheless, the amount of canthaxanthin in the serum increased when carotenoid was associated with phospholipids plus fish oil. When canthaxanthin is transported by lecithin plus fish oil, the amount of phospholipids, cantaxanthin, and cholesterol deposited in muscle increased but not significantly. The highest apparent canthaxanthin digestibility coefficient was obtained when canthaxanthin was carried by lecithin plus fish oil. The administration of canthaxanthin carried by phospholipids improved its accumulation in the muscle of rainbow trout. This accumulation could be enhanced if the time of administration of canthaxanthin is increased.

Effect of canthaxanthin content of the maternal diet on the antioxidant system of the developing chick.

1. Effects of canthaxanthin supplementation of the maternal diet on the antioxidant system of the developing chick were investigated. 2. Three hundred and twenty female broiler breeder birds were housed in one of 4 controlled environment rooms with 3 replicates for all treatments, with the exception of the control treatment of which there were 4 replicates. All birds received one of 5 diets: control low xanthophyll diet, or the same diet supplemented with 3, 6, 12 or 24 mg/kg canthaxanthin in the form of Carophyll Red. At 30 weeks of age 60 eggs from each of the 5 groups were incubated. At d 16 of the embryo development, at d 1 and d 7 posthatch tissue samples were collected and analysed by HPLC-based methods. 3. Canthaxanthin accumulation in the egg yolk was proportional to dietary content. Furthermore, at 12 to 24 mg/kg canthaxanthin was associated with an increase in gamma-tocopherol concentration in the egg yolk. Canthaxanthin was transferred from the egg yolk to the developing embryo and, as a result, its concentration in the liver of the embryo at 16 and in 1-d-old chicks was increased. Even at d 7 posthatch canthaxanthin concentration in the chicken liver was elevated. 4. Canthaxanthin supplementation of the maternal diet at 12 mg/kg was associated with an increased alpha-tocopherol concentration in the liver of 1-d-old chicks and resulted in decreased tissue susceptibility to lipid peroxidation. 5. Canthaxanthin supplementation at 6 to 24 mg/kg was also associated with a delay in alpha-tocopherol depletion from the liver for 7-d posthatch. As a result of the increased canthaxanthin and vitamin E concentrations in the liver of 7-d-old chicks, tissue susceptibility to lipid peroxidation decreased. 6. The results support an idea that dietary carotenoids can modulate antioxidant systems of the developing chicken.

Carotenoid incorporation into natural membranes from artificial carriers: liposomes and beta-cyclodextrins.

Liposomes and beta-cyclodextrin (beta-CD) have been used as carriers for the incorporation of three dietary carotenoids (beta-carotene (BC), lutein (LUT) and canthaxanthin (CTX)) into plasma, mitochondrial, microsomal and nuclear membrane fractions from pig liver cells or the retinal epithelial cell line D407. The uptake dynamics of the carotenoids from the carriers to the organelle membranes and their incorporation yield (IY) was followed by incubations at pH 7.4 for up to 3 h. The mean IYs saturated between 0.1 and 0.9 after 10-30 min of incubation, depending on membrane characteristics (cholesterol to phospholipid ratio) and carotenoid specificity. Mitochondrial membranes (more fluid) favour the incorporation of BC (non-polar), while plasma membranes (more rigid) facilitate the incorporation of lutein, the most polar carotenoid. A high susceptibility of BC to degradation in the microsomal suspension was observed by parallel incubations with/without 2,6-di-t-buthyl-p-cresol (BHT) as antioxidant additive. The beta-CD carrier showed to be more effective for the incorporation of lutein while BC was incorporated equally into natural membranes either from liposomes or from cyclodextrins. The presence of cytosol in the incubation mixture had no significant effects on the carotenoid incorporations.

Absorption of canthaxanthin by the rat is influenced by total lipid in the intestinal lumen.

In this study the effect of luminal lipid on the absorption of canthaxanthin (CTX) was investigated using the lymph duct cannulated rat. Treatments were emulsions designed to deliver increasing amounts of olive oil (10, 30, 50, 70, or 90 mg/h) and CTX (12.5 nmol/h). Emulsions were continuously infused into the duodenum for 12 h, and lymph was collected during the final 6 h of infusion for analysis. As the amount of lipid in the emulsion increased, a linear increase in the absorption of CTX was observed. The recovery of CTX in the lymph when infused with 10 mg/h olive oil was 14.2 +/- 1.2% and with 90 mg/h was 26.9 +/- 5.7%. The efficiency of CTX absorption nearly doubled by increasing the amount of lipid infused with CTX. The correlation between lipid load and CTX absorbed was r= 0.85. We conclude that luminal lipid load affects CTX absorption.

Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites.

PURPOSE: To establish the threshold level of canthaxanthin crystals in the retina of cynomolgus monkeys. To correlate the spatial distribution of all-trans canthaxanthin and its metabolites with the grade of crystals. METHODS: Monkeys were orally administered 0, 0.2, 0.6, 1.8, 5.4, 16.2, and 48.6 mg/kg body wt canthaxanthin daily for 2.5 to 3 years. A second group of monkeys were administered 200 and 500 mg/kg body wt/d for 5 years. Ophthalmoscopy, electroretinography (ERG), retina and carotenoid analysis were performed as previously reported. RESULTS: Crystals in the retina periphery were observed by ophthalmoscopy preterminally only in the extreme high doses of 200 to 500 mg/kg body wt/d. There were no adverse effects on visual functions as measured by ERG. Crystals in the peripheral retina, and/or in the macula, were detected microscopically in all canthaxanthin treated groups except at the lowest dose of 0.2 mg/kg body wt/d. The grade of crystals increased up to a dose of 16.2 mg/kg body wt/d. Dose-dependent increases in canthaxanthin content also were noted in the retina, the liver, and in plasma. All-trans canthaxanthin was the major compound in the peripheral and paracentral retina of very highly dosed animals, where its concentration correlated largely with the grade of inclusions. In the macula, 4'-OH-echinenone was the dominant canthaxanthin metabolite. CONCLUSIONS: The grade of crystals in monkey retinas was dose dependent with a threshold level at 0.6 mg canthaxanthin/kg body wt/d. It correlated in the retinal periphery with the concentrations of all-trans-canthaxanthin and in the macula with its metabolites.

A comparison of the anticancer activities of dietary beta-carotene, canthaxanthin and astaxanthin in mice in vivo.

The anticancer activities of beta-carotene, astaxanthin and canthaxanthin against the growth of mammary tumors were studied in female eight-wk-old BALB/c mice. The mice were fed a synthetic diet containing 0, 0.1 or 0.4% beta-carotene, astaxanthin or canthaxanthin. After 3 weeks, all mice were inoculated with 1 x 10(6) WAZ-2T tumor cells into the mammary fat pad. All animals were killed on 45 d after inoculation with the tumor cells. No carotenoids were detectable in the plasma or tumor tissues of unsupplemented mice. Concentrations of plasma astaxanthin (20 to 28 mumol/L) were greater (P < 0.05) than that of beta-carotene (0.1 to 0.2 mumol/L) and canthaxanthin (3 to 6 mmol/L). However, in tumor tissues, the concentration of canthaxanthin (4.9 to 6.0 nmol/g) was higher than that of beta-carotene (0.2 to 0.5 nmol/g) and astaxanthin (1.2 to 2.7 nmol/g). In general, all three carotenoids decreased mammary tumor volume. Mammary tumor growth inhibition by astaxanthin was dose-dependent and was higher than that of canthaxanthin and beta-carotene. Mice fed 0.4% beta-carotene or canthaxanthin did not show further increases in tumor growth inhibition compared to those fed 0.1% of each carotenoid. Lipid peroxidation activity in tumors was lower (P < 0.05) in mice fed 0.4% astaxanthin, but not in those fed beta-carotene and canthaxanthin. Therefore, beta-carotene, canthaxanthin and especially astaxanthin inhibit the growth of mammary tumors in mice; their anti-tumor activity is also influenced by the supplemental dose.

Supplementing ferrets with canthaxanthin affects the tissue distributions of canthaxanthin, other carotenoids, vitamin A and vitamin E.

To study the effects of canthaxanthin supplementation on the tissue distribution of canthaxanthin, other carotenoids, vitamin A and vitamin E, 26 spayed female ferrets (2 mo of age) were used. Ferrets were assigned to receive a commercial ferret diet and a gavage of canthaxanthin [50 mg/(kg body wt.d)] or a gavage of placebo beadlets (0 mg canthaxanthin) 5 d/wk. Serum canthaxanthin concentrations in the canthaxanthin-fed group increased from 0 at baseline to 37.76 +/- 5.34 nmol/L trans and 77.10 +/- 12.60 nmol/L cis canthaxanthin at 12 mo. Further accumulation of canthaxanthin did not occur with continuous dosing. After 2 y of receiving canthaxanthin beadlets by gavage, the ferrets did not show a detectable concentration of canthaxanthin in the eyes, nor did they have clinical signs of toxicity. Canthaxanthin concentrations were highest in liver, with high concentrations also seen in fat, lung and small intestine. The sum of alpha and beta-carotene concentrations detected in livers was significantly higher in the canthaxanthin-fed group than in the placebo-fed group, but not significantly higher when individual carotenes were compared. However, alpha-tocopherol concentrations in the livers and lungs and lutein/zeaxanthin in the fats of the ferrets fed canthaxanthin were significantly lower than in those fed the placebo. Retinoid concentrations in tissues of the ferrets fed canthaxanthin were not different from those of the placebo-fed group. The effects of canthaxanthin supplementation on other antioxidants and vitamin A nutrients demonstrate either a synergistic or antagonistic relationship, depending on the specific tissue assayed.

Comparative absorption and transport of five common carotenoids in preruminant calves.

Preruminant calves, maintained in a monogastric state by feeding an all-liquid diet, were used to compare the serum appearance and lipoprotein transport of five different carotenoids over 144 h. Thirty newborn calves were fed milk replacer for 1 wk and then randomly assigned to six groups (n = 5), with each group receiving a single 20-mg oral dose of beta-carotene in water-soluble beadlets, canthaxanthin in water-soluble beadlets, lutein in oil, lycopene in oil, crystalline alpha-carotene in oil or crystalline beta-carotene in oil as part of a morning meal. Serial blood samples were taken by jugular puncture for up to 1 wk post-dosing. Lipoprotein separation and analysis were completed with selected animals. All carotenoids were absorbed, but in variable amounts. At peak serum carotenoids levels, HDL contained 70-90% of the carotenoids. Canthaxanthin and lutein peaked earlier in serum (8 and 12 h) than did the less polar lycopene, alpha-carotene, and beta-carotene (16, 24 and 24 h). Canthaxanthin and lutein were also cleared more quickly from the serum. Serum concentrations of alpha-carotene and lycopene displayed slower disappearance rates than did beta-carotene. The peak serum level (nmol/L +/- SEM) of canthaxanthin (392 +/- 136) was lower than that of beta-carotene (1245 +/- 425), and carotenoids levels of calves receiving these commercial beadlet sources were higher than the serum levels of calves receiving beta-carotene (45 +/- 17.5), alpha-carotene (42 +/- 18.0), lutein (51 +/- 9.5) and lycopene (18 +/- 4.6), which were fed in oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of beta-carotene and canthaxanthin after ingestion of individual and combined doses by human subjects.

OBJECTIVE: This study investigated effects of ingestion of a combined dose of beta-carotene and canthaxanthin on their individual pharmacokinetics in serum. METHODS: During three 5-day study periods, two subjects ingested either a 25 mg dose of beta-carotene, a 25 mg dose of canthaxanthin, or a combined dose of 25 mg each of beta-carotene and canthaxanthin. Pharmacokinetics of the individual and combined doses were compared within subjects. RESULTS: Ingestion of a concurrent beta-carotene dose reduced the peak serum canthaxanthin concentration by 38.8 +/- 6.5%, and the 24- and 72-hour areas under the serum canthaxanthin concentration-time curves by 38.1 +/- 6.4 and 34.4 +/- 7.4%, respectively. The suggested antagonism between beta-carotene and canthaxanthin was not reciprocal; beta-carotene inhibited the appearance of canthaxanthin in serum but canthaxanthin did not inhibit the appearance of beta-carotene. CONCLUSION: Our data suggest that ingestion of a combined pharmacologic dose of beta-carotene and canthaxanthin reduces the bioavailability of the canthaxanthin dose.

[Canthaxanthin retinopathy. Follow-up of over 6 years]. / Canthaxanthin-Retinopathie. Verlaufskontrolle nach über 6 Jahren.

After long-term treatment with high dosages, canthaxanthin causes a characteristic retinopathy with circular, macula surrounding crystals. As changes in retinal functionning disappear relatively easily after withdrawal of the drug, the crystals dissolve rather slowly--over about several years. Five patients showing a profound crystalline retinopathy were re-examined with an average of 69.7 months after withdrawal of the canthaxanthin-containing drug. Three of the patients were treated for erythropoetic protoporphyria (EPP) with Phenoro (2/5 beta-carotene, 3/5 canthaxanthin), two sisters took a canthaxanthin-containing formulation (1/8 beta-carotene, 7/8 canthaxanthin) for cosmetic reasons. Two female patients complained about an increased glare sensitivity, which was explainable for one of them with a subcapsular cataract. The retinal crystals decreased quite differently. Minor deffects of the retinal pigment epithelium remained unchanged in two patients. They increased slightly in the female patient with the smallest crystal formation but highest plasma cholesterol. Shortly after withdrawal of the drugs usually an increase of a-wave amplituded of the electroretinograms was found. The a-waves returned to normal and the b-wave amplitudes showed an increase up to the final control paralleling the reduction of the retinal crystals. A- and b-wave peak latencies which were prolonged under treatment returned to normal.

Comparative accumulations of labelled carotenoids (14C-astaxanthin, 3H-canthaxanthin and 3H-zeaxanthin) and their metabolic conversions in mature female rainbow trout (Oncorhynchus mykiss).

1. One force-fed meal containing labelled 14C-astaxanthin (14C-Ax) and 3H-canthaxanthin (3H-Cx) or 3H-zeaxanthin (3H-Zx) was given to eight mature female rainbow trout. Ninety-six hours after the test meal ingestion, trout were killed and liver, skin, muscle and ovaries were dissected out. 2. Ax accumulated slightly more in muscle than Cx but in all tissues Ax and Cx were very significantly more concentrated than Zx. 3. 3H-Zx metabolites were found only in the liver, whereas 14C-phoenicoxanthin was the only metabolic pigment from 14C-Ax detected and was found in all investigated tissues. 4. 3H-Ax was found in the liver of all trout indicating that 3H-Cx and 3H-Zx were Ax precursors, and that salmonids probably possess carotenoid oxidative pathways unknown until now. 5. Labelled retinol1 and retinol2 were detected only in the liver and 3H-Zx was largely the predominant precursor of these two vitamin A forms.

The use of high-performance liquid chromatography for studying pigmentation.

The use of HPLC has established that chickens possess unexpected metabolic abilities to acylate, deacylate, reduce, and oxidize carotenoids. The use of HPLC permits more consistent and more economic pigmentation of carcasses and of egg yolks. Hopefully, the use of HPLC will raise pigmentation from an art to a science. Apparently, HPLC will be an essential tool in terms of future efforts to understand and master the process of poultry pigmentation.

Measurement of malabsorption of carotenoids in chickens with pale-bird syndrome.

Because pale-bird syndrome (PBS), defined as the failure of birds to realize the color potential of their diet, has been demonstrated to be caused by malabsorption or by hyperexcretion of carotenoids, a method for measuring malabsorption of carotenoids would be useful. The absorption of dietary canthaxanthin, a red diketocarotenoid, into serum during aflatoxicosis was measured in an experiment with a 2 x 9 factorial arrangement of treatments (0 and 5 micrograms of aflatoxin/g of diet; serum collected at 0, 2, 4, 6, 8, 10, 12, 14, and 24 h after a standard meal fed to four groups of 10 3-wk-old birds). Serum canthaxanthin levels determined by HPLC attained plateau values between 8 and 14 h after the meal. The absorption of canthaxanthin was depressed significantly (P less than .05) in birds with aflatoxicosis from 4 to 24 h after feeding the standard meal. Four field flocks diagnosed as having PBS were tested for malabsorption by intubating 10 birds with a standard amount of canthaxanthin and measuring serum canthaxanthin 12 h later. One flock had about 85% normally pigmented birds and 15% extremely pale birds, the second flock had a coccidiosis history, the third had a Newcastle disease history, and the fourth had a history of both coccidiosis and Newcastle disease. The flocks were 5- to 6-wk-old, received feed of the same manufacture, and their disease outbreaks had occurred 2 wk earlier.(ABSTRACT TRUNCATED AT 250 WORDS)