Vol. 38:69-96 (Volume publication day August 2018) https://doi.org/10.1146/annurev-nutr-082117-051628

Patrick Borel and also Charles Desmarchelier

Recent data have presented that interindividual variability in the bioavailability of vitamins A (β-carotene), D, and E, and carotenoids (lutein and also lycopene), and that of phytosterols, is modulated by single nucleotide polymorphisms (SNPs). The determined SNPs are in or close to genes connected in intestinal absorb or efflux of this compounds, and also in genes affiliated in your metabolism and transport. The phenotypic result of every SNP is generally low, however combinations that SNPs can describe a significant part the the variability. Nevertheless, outcomes from this studies have to be thought about preliminary since they have not been validated in other cohorts. Guidelines for future studies are listed to ensure that sound associations space elucidated that deserve to be used to develop consolidated hereditary scores the may permit recommended dietary allowances to be tailored to individuals or groups by taking right into account the multiloci genotypic signature of civilization of different ethnic beginning or also of individuals.

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absorption, carotenoids, lycopene, lutein, polymorphisms, phytosterols


Vitamins space micronutrients: they are vital in minute quantities (vitamin A (preformed vitamin A, i.e., retinol and its esters, and also provitamin A carotenoids, i.e., mostly β-carotene, α-carotene, and β-cryptoxanthin)

vitamin D (cholecalciferol and ergocalciferol)

vitamin E (tocopherols and also tocotrienols)

vitamin K (phylloquinone and menaquinones)

Phytochemicals room naturally arising plant chemicals. Thousands are typically found in the person diet, usually in minute amounts (108 and 111 for reviews).

Fat-soluble vitamins and also terpenoids room lipids, and as such, your fate in the gastrointestinal tract throughout digestion and their absorption by enterocytes re-superstructure some usual mechanisms (2, 69). The exploration of the involvement of proteins in the uptake and absorption of these compounds by the human being body (112, 131) has actually led to new hypotheses aimed at explaining the reasonably wide-ranging interindividual variability in their bioavailability and also health effects. Indeed, the many proteins affiliated in your bioavailability have led to suggestions that sports in the genes encoding for these proteins could modulate the expression or activity of these proteins and could, in turn, affect the bioavailability of this compounds. Therefore, this review intends to current what is known about the effects of genetic variation ~ above the bioavailability of fat-soluble vitamins and phytochemicals in humans and also to comment on how future studies can be carried out, and the potential applications that this fast-moving field. We focus on the compounds because that which over there are sufficient data, the is, vitamins A <β-carotene (βC)>, D, and also E, the carotenoids lycopene and lutein, and PS.


2.1. Vitamin E

Vitamin E (VE) is the generic term that describes compounds exhibiting qualitatively the biological activity of α-tocopherol. These encompass eight naturally developing molecules: 4 tocopherols (α, β, γ, and δ) and four tocotrienols (α, β, γ, and also δ) (Figure 1). Naturally occurring and chemically synthetized tocopherols are not identical: fabricated tocopherol is generally a racemic mixture the eight stereoisomers and is named all-rac-tocopherol, whereas herbal tocopherols exist only in the RRR configuration. Additionally, fabricated tocopherol is often noted as an ester to defend the phenol group versus oxidation and thus rise its shelf life (126).

Figure 1

The many abundant creates of VE in diet in occurred countries room α- and also γ-tocopherol, and also they are found at the highest possible concentrations in human blood and tissues (144). VE is uncovered at relatively high concentrations in vegetable oils and also nuts, yet it is likewise present in various other food matrices. In the unified States, roughly 70% of VE input is accounted for by γ-tocopherol because of the high consumption of food resources rich in γ-tocopherol in the common diet (e.g., soybean oil, corn oil) (71). The current United claims recommended dietary pin money (RDA) the VE for healthy and balanced adults is 15 mg/day, however it is estimated that >90% that men and >96% women in the unified States carry out not consume the estimated average needs (EARs) (125). Data indigenous a study published in 2012 point to comparable inadequacies in number of European countries (127). A systematic review of global α-tocopherol status has actually pointed to a reasonably high ubiquity of VE deficiency, with 13% of the participants exhibiting serum α-tocopherol concentrations 66), and also only 21% the the participants getting to serum α-tocopherol concentrations >30 μmol/L (107), which has actually been proposed together a criterion because that VE adequacy (91).

VE is quantitatively the key lipid-soluble antioxidant in mammalian blood and tissues (27). It acts as a chain-breaking antioxidant, especially versus peroxyl radicals, and is thus important in preserving the verity of the long-chain polyunsaturated fat acids discovered in cell membranes (27). Within the previous 15 years, that has likewise been shown to exert nonantioxidant activities (146): modulation of gene expression (78, 145), inhibition of cell proliferation (72), and also regulation that bone fixed (51). Since oxidative stress has been implicated in the etiology of numerous diseases, for example, cardiovascular diseases and cancers, numerous epidemiological studies have actually investigated the association in between VE dietary intake or status and also the incidence of these diseases, and these studies have actually reported advantageous associations (97, 106, 110). However, many randomized controlled trials have actually failed to present a benefit of VE supplementation on the incidence the these diseases (29, 124). Number of explanations have been placed forward, consisting of an lack of an impact of VE supplementation ~ above these illness (56), a an unfavorable effect of α-tocopherol supplementation top top the bioavailability of other VE vitamers (36), and also the absence of populace stratification by VE status or oxidative stress (124). The has additionally been said that high interindividual variability the α-tocopherol bioavailability may have actually interfered through the impacts of VE supplementation (25) and that the capability to benefit from VE supplementation relies on a participant"s genotype (15, 93, 147).

2.2. Vitamin D

Vitamin D (VD) is the share term that refers to compounds exhibiting antirachitic activity. The two main VD vitamers room cholecalciferol and also ergocalciferol (Figure 1). In animals, VD3 is synthesized through the exposure of 7-dehydrocholesterol in the skin to UVB light, whereas in fungi, VD2 is synthesized through the exposure that ergosterol come UVB light. In humans, VD photosynthesis different widely and also depends on many factors, because that example, the expression of sun exposure, time that day, latitude, season, environment composition, clothing, sunscreen use, and skin pigmentation, however a majority of individuals require part dietary VD, one of two people from VD-rich foodstuffs or from supplements, to with an sufficient VD status. VD3 is the key dietary source of VD and is acquired in far-ranging amounts indigenous food, such as milk and dairy products, fatty fish, meat, and also eggs (61). The us RDA for healthy and balanced adults is 15 μg/day (assuming minimal sunlight exposure), and data allude to dietary intakes listed below recommended levels for >75% that the populace in several arisen countries (127). Follow to the findings of the nationwide Health and Nutrition Examination inspection 2005–2006, 37% the the US population uses a dietary complement containing VD (9).

VD is a prohormone that demands two hydroxylations to come to be active. In the liver, that is convert by cytochrome P450 (CYP) household 2 subfamily R member 1 (CYP2R1) come 25-hydroxycholecalciferol <25(OH)D>, i beg your pardon is the key circulating VD form, the concentration of i m sorry is measured to assess VD status. Following its move via the bloodstream bound come vitamin D binding protein (DBP), the is converted in the kidney through CYP household 27 subfamily B member 1 (CYP27B1) to 1,25-dihydroxycholecalciferol <1,25(OH)2D> (34). This metabolite exerts both nongenomic and also genomic effects via the vitamin D receptor (VDR), and also far much more than 1,000 target genes have been figured out (30). VD is important for bone health and also for regulation blood calcium and phosphate concentrations, but it is also involved in other biological functions, such together immunity, cabinet proliferation, and also apoptosis. In a Mendelian randomization analysis, VD condition was negatively associated with all-cause and cancer mortality (3).

2.3. Carotenoids

Carotenoids room lipid phytochemicals belonging to the tetraterpene family. There room two classes: carotenes that room nonoxygenated carotenoids (e.g., α- and also β-carotene, lycopene) and xanthophylls that are oxygenated carotenoids (e.g., lutein, zeaxanthin, β-cryptoxanthin). Carotenoids are herbal pigments, through colors varying from red to yellow, and also are created in all photosynthetic biology (bacteria, algae, and also plants), as well as in part nonphotosynthetic bacteria and fungi. Castle are connected in many organic functions, such as photosynthesis, photoprotection, photomorphogenesis, development, and hormone synthetic (102), and they likewise participate in enhancing the visual attraction of these organisms.

More than 700 different carotenoids have been identified, but only about 40 are existing in far-ranging amounts in the human diet. Total and also individual carotinoid intake is very variable both within and also between populations, and also it greatly reflects fruit and vegetable consumption. Data native 37,846 European inhabitants reported a mean complete carotenoid intake of 10±4 mg/day (119). The 6 carotenoids found in the highest possible concentrations in person blood room those found in the highest possible quantities in the person diet, the is, βC, lycopene, and also lutein (Figure 1), and β-cryptoxanthin, α-carotene, and zeaxanthin (77). Although there room no RDAs because that carotenoids, greater consumption is generally recommended.

Following enzymatic cleavage through β-carotene oxygenase 1 (BCO1), α- and β-carotene, and β-cryptoxanthin, deserve to be converted to retinol in the human body and also hence are described as provitamin A (proVA) carotenoids. The RDA for VA in France is 600- and also 800-μg retinol task equivalents (RAE) per day for, respectively, women and also men (US RDA, 700 and 900 μg/day, respectively). RAE have been developed to account for the variability in carotenoid bioavailability, relying on the food matrix in which they are incorporated and also the performance of their conversion to retinol adhering to their enzymatic cleavage (56). Current RAE are as follows: 1-μg RAE = 1-μg retinol = 2-μg all-trans-βC native supplements = 12-μg all-trans-βC indigenous food = 24-μg α-carotene or β-cryptoxanthin from food.

The donation of proVA carotenoids as a resource of VA relies on diet habits, yet a meta-analysis has displayed that they stand for 35% of full VA entry in arisen countries (βC, 86%; α-carotene, 10%; β-cryptoxanthin, 4%) (135). Although frank VA deficiency is rare in emerged countries, data allude to dietary intakes below recommended level in large parts that the populace of several occurred countries (127). Nevertheless, VA deficiency remains a publicly health problem in developing countries, mainly as result of inadequate VA intake brought about by insufficient accessibility to VA-rich foodstuffs (i.e., animal products). The is estimated that about one-third of youngsters are affected (90), but women of reproductive period are likewise at hazard of deficiency. VA deficiency compromises the immune system, hence worsening the outcomes of typical childhood epidemic (e.g., measles, malaria). The earliest symptom of VA deficiency is impaired night vision, which in extreme instances leads come irreversible blindness. According to the human being Health Organization, night blindness is estimated to affect 250,000–500,000 children each year, 50% the whom die within the following year.

The xanthophylls lutein and zeaxanthin are existing at high concentration in the human being macula lutea (the yellow spot of the retina), and there is a farming body of evidence arguing that they exert a certain biological duty in the eye. Numerous studies have actually demonstrated that they boost visual acuity and also can quench 400–450-nm event blue light, i beg your pardon is harmful come photoreceptors (87). Several various other studies have additionally suggested the their consumption diminishes the incidence that cataract and age-related macular degeneration (6, 13).

Lycopene is the colors responsible for the red color of tomatoes and tomato products. Both dietary intake and greater blood concentrations have been negatively linked with the danger of prostate cancer (32, 133) and also cardiovascular an illness (33). Since oxidative stress has been implicated in the etiology of this diseases, lycopene has actually been argued to exert that protective impacts through the antioxidant properties, which have been well identified in vitro (75). However, lycopene also exhibits biological activity independent that its antioxidant effects: the modulates inflammation (49, 55, 86) and also reduces the effectiveness of cholesterol absorption (148), and also several studies imply that the metabolic products additionally exert nonantioxidant organic effects (8, 54, 55, 92).

2.4. Phytosterols

PS room plant-derived sterols through structural similarity to cholesterol, however with side chain modifications and ring saturations. PS are separated into 2 classes: Sterols, likewise known together Δ5-sterols, are unsaturated at place 5 in the sterol ring, vice versa, stanols, additionally known as 5α-sterols, have actually a saturated sterol ring (Figure 1) (105). PS are uncovered in fruits, vegetables, nuts, and also oils, with Δ5-sterols the many abundant class.

The input of PS is between 200 and 400 mg/day in the usual diet in emerged countries, depending upon dietary habits, i m sorry is close come the typical cholesterol intake. Most ingested PS are Δ5-sterols, with the most abundant being sitosterol. High concentration of PS are found in oils, such together corn and also sunflower oils, and additionally in almonds, beans, corn, and also wheat.

Due to your structural similarity, PS and also cholesterol complete for incorporation right into mixed micelles and subsequent uptake by the enterocyte. Overall, numerous meta-analyses have shown that PS added to food result in a far-reaching decrease in low-density lipoprotein (LDL) cholesterol (73, 108). No far-ranging differences in terms of impact were observed in between Δ5-sterols and also 5α-sterols.


The bioavailability of one ingested molecule is usually characterized as the family member amount that the molecule or among its metabolites that reaches the systemic circulation or its site of action. In practice, biologist use different methods to evaluate it. For example, pharmacologists generally estimate the bioavailability of one orally administered drug by measuring the postprandial blood concentration of the drug or one of its metabolites. Nutritionists use this technique as fine as alternate methods. Indeed, they also estimate the bioavailability that a molecule by measuring the increase in the fasting blood concentration complying with either acute or chronic supplementation. They also estimate bioavailability by measuring the rise in concentration in a tissue whereby it is assumed to exert its biological action, for example, measure carotenoids in the skin. Additionally, they estimate tissue bioavailability by quantifying a marker, the level of which correlates through the tissue concentration that the studied molecule, for example, measure macular colours optical density, i m sorry is used as a marker of xanthophyll concentration in the macula lutea. Techniques using secure isotopes of fat-soluble vitamins and also phytochemicals permit nutritionists to measure an ext accurately the amount of these absorbed through the diet (95, 128). It need to be emphasized that many approaches, with the exemption of the last mentioned, measure only the relative bioavailability of fat-soluble vitamins and also phytochemicals.

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Different approaches can be used to evaluate the bioavailability the the same molecule. Because that example, lutein bioavailability deserve to be approximated by measuring postprandial chylomicron concentration (24), plasma concentration after a lutein-rich test meal, the permanent plasma lutein solution to everyday lutein supplementation (58), or variation in macular colours optical density after permanent lutein supplementation (19). The relative weights the the metabolic procedures modulating the bioavailability the fat-soluble vitamins and phytochemicals different according come the assessment technique used. Thus, studies investigating genetic variations associated with variability in the bioavailability the fat-soluble vitamins and phytochemicals are likely to yield various results if various bioavailability assessment approaches are used.

The bioavailability the fat-soluble vitamins and phytochemicals counts on several successive steps, from their transfer from the food or supplement through which they space ingested to the tissues whereby their concentration is measured. To put into perspective several of the genetic associations disputed in this review, we briefly explain these steps, focusing on the protein that have the right to significantly affect the bioavailability the fat-soluble vitamins and also phytochemicals. (Readers have the right to find much more detailed information in the reviews in recommendations 16, 18, 20, 21, 40, and also 112.) The very first step is to extract the compounds native food or supplements and transfer castle to mixed micelles; the is, they undergo micellization (Figure 2). The performance of this action is just partial, and the fraction of fat-soluble vitamins and phytochemicals the is therefore made potentially accessible for absorption is referred as the bioaccessible fraction. The second step is the absorb of these compounds or your metabolites, developed during digestion, through the enterocyte (Figure 3). A 3rd step is your resecretion in the intestinal lumen. This procedure can be quantitatively essential for part fat-soluble vitamins and phytochemicals, for example, PS, which room excreted native the enterocyte by the ATP (adenosine triphosphate) binding cassette subfamily G members 5 and also 8 (ABCG5 and also ABCG8) heterodimer. The compound that stay in the minister cell space then transported throughout the enterocyte to be secreted at the basolateral side, greatly in chylomicrons but additionally in minister high-density lipoprotein (HDL). Parent fat-soluble vitamins and also phytochemicals and also their metabolites are largely secreted in the lymph fluid, but some less apolar metabolites are additionally secreted in the portal vein. Following their uptake, metabolism, and secretion right into the bloodstream by the liver, the blood metabolism of different fat-soluble vitamins and phytochemicals and also their metabolites differs due to the fact that some—such as VE, carotenoids, and also PS—are transported in lipoproteins, if others space transported by particular proteins; for example, retinol is transported by the retinol binding protein 4–transthyretin facility (RBP4–TTR) and also 25(OH)D by DBP. Number of different factors can influence these processes, and furthermore, the fact that plenty of proteins space implicated in the bioavailability the fat-soluble vitamins and also phytochemicals (Figure 3) likely explains the high interindividual variability that has been observed for all of those that have actually been studied. Indeed, after standardized test meals well-off in fat-soluble vitamins and also phytochemicals were given to a group of healthy and balanced participants, the coefficient of sports of the blood response, i beg your pardon was provided as a mite of their bioavailability, ranged from 47% because that VD provided as a complement to 137% because that lutein offered in tomato puree (22–25, 41).