Summary
1. Introduction
Vitamin C (ascorbate) is a vital water-soluble micronutrient in people and is obtained via the weight-reduction plan primarily from vegatables and fruits [1]. In vivo, it acts as a cofactor for quite a few biosynthetic enzymes required for the synthesis of amino acid-derived macromolecules, neurotransmitters and neuropeptide hormones [2], and for numerous hydroxylases concerned within the regulation of gene transcription and epigenetics [3,4]. Vitamin C is concentrated from the plasma into the physique’s organs and is present in significantly excessive concentrations within the pituitary and adrenal glands and within the corpus luteum [5], though skeletal muscle, mind, and liver comprise the most important physique swimming pools [6]. Most animals can synthesize vitamin C from glucose within the liver [7]; nevertheless, people and a small number of animal species have misplaced the power to synthesize vitamin C as a result of mutations within the gene encoding l-gulono-γ-lactone oxidase, the terminal enzyme within the vitamin C biosynthetic pathway [8]. Subsequently, an enough and common dietary consumption is important to stop hypovitaminosis C and the doubtless deadly deficiency illness, scurvy [9].
Within the mid 1700s the Royal Navy surgeon James Lind carried out managed dietary trials and decided that citrus fruit might remedy people with scurvy (reviewed in [10]). Nonetheless, it wasn’t till the early 1900s that experimental scurvy was first produced in guinea pigs via dietary restriction and proven to be prevented by feeding the animals recent vegatables and fruits. Within the early Thirties vitamin C was remoted from fruit and greens and adrenal cortex and was named “hexuronic acid”, which was proven to remedy scurvy in guinea pigs and was subsequently renamed ascorbic acid to replicate its anti-scorbutic properties. Vitamin C was first chemically synthesized in 1933 [10] and, for the reason that mid Thirties, the query of the comparative bioavailability of artificial versus pure, food-derived vitamin C in animal fashions and human topics has been a degree of consideration.
The bioavailability of dietary vitamin C represents the proportion of the micronutrient that’s absorbed by the intestines and is offered for metabolic processes throughout the physique. In vivo vitamin C ranges are a perform of uptake, metabolism, and excretion (see [11] for a superb assessment of those processes). Vitamin C is actively transported into the physique through two sodium-dependent vitamin C transporters, SVCT1 and SVCT2 [12,13]. These transporters exhibit totally different tissue distributions and uptake kinetics. SVCT1 is expressed in epithelial tissues and is primarily accountable for intestinal uptake and renal reabsorption of vitamin C, the latter serving to to keep up complete physique homeostasis [13]. SVCT2 is expressed in specialised and metabolically energetic tissues and is required for supply of vitamin C to tissues with a excessive demand for the vitamin both for enzymatic reactions [2] and/or to assist shield these tissues from oxidative stress [13]. Each of those transporters present considerably extra affinity for the l- versus
d-isoform of vitamin C (Determine 1) [12,14], and this selectivity possible explains earlier observations of considerably decrease tissue accumulation and anti-scorbutic exercise of d-ascorbic acid in guinea pigs [15,16]. Though d-ascorbic acid is a generally added meals preservative [17], administration of d- and l-ascorbic acid collectively doesn’t have an effect on the bioavailability of the latter in people [18].
Via its motion as a decreasing agent and antioxidant, ascorbate undergoes one and two electron oxidations to supply the ascorbyl radical and dehydroascorbic acid (DHA) (Determine 1). Current analysis has proven that DHA might be taken up by the facilitative glucose transporters GLUT2 and GLUT8 within the small gut [19]. Cells are additionally capable of transport DHA through GLUT1 and GLUT3 [20,21], adopted by intracellular discount to ascorbate [22,23]. Nonetheless, transport through the GLUTs is in competitors with glucose which is at comparatively excessive concentrations all through the physique and though totally different vegatables and fruits have been proven to include comparatively excessive quantities of DHA [24], the in vivo contribution of DHA is unsure as a result of its minimal circulating and organ ranges [25,26] (though white blood cells could also be an exception to this) [27,28].
Artificial and food-derived vitamin C is chemically equivalent. Nonetheless, fruit and greens are wealthy in quite a few micronutrients (nutritional vitamins and minerals), dietary fiber, and phytochemicals (e.g., bioflavonoids), and the presence of a few of these could have an effect on the bioavailability of vitamin C. Vitamin C has lengthy been identified to work together with vitamin E by decreasing the tocopheroxyl radical and regenerating native tocopherol [29]. Some fruit, similar to kiwifruit, include comparatively excessive quantities of vitamin E and one animal research has indicated that vitamin E is ready to protect vitamin C in vivo [30]. Meals-derived (and artificial) vitamin C is well-known to extend non-heme iron uptake and physique standing, possible through its capacity to scale back iron from its ferric to ferrous state [31,32]. Nonetheless, whether or not iron can have an effect on vitamin C bioavailability is much less clear [33,34,35]. Though iron has been proven to extend the uptake of vitamin C in cultured intestinal cells [33], human intervention research have proven no impact of iron consumption on vitamin C bioavailability [34,35]. One research has indicated that particular dietary fibers, similar to hemicellulose and pectin, could have an effect on the excretion of vitamin C [36], nevertheless, their affect on vitamin C uptake was not decided.
Plant-derived flavonoids have been of curiosity for the reason that mid Thirties, after they have been initially known as “vitamin P”, primarily as a result of their impact on vascular permeability [37]. On the time, there was a lot debate within the literature relating to the function of “vitamin P” in experimental [38,39,40,41,42] and human scurvy [37,43,44,45]. Flavonoids can act as antioxidants through direct scavenging of free radicals [46,47] and/or chelation of redox-active metallic ions [48,49]. In consequence, it has been instructed that flavonoids could “spare” vitamin C and, thus, improve its bioavailability. Flavonoids have been proven to inhibit the in vitro oxidation of vitamin C [48,49,50,51], nevertheless, the in vivo relevance of metal-ion mediated oxidation of vitamin C is more likely to be minimal as free metallic ions are largely sequestered within the physique [52]. Whether or not flavonoids can have an effect on vitamin C uptake in vivo is unsure as a result of low plasma bioavailability of those compounds [53]. Thus, any interplay of flavonoids with vitamin C could be anticipated to happen primarily within the intestinal lumen previous to energetic uptake.
Of notice, a number of in vitro research have proven that numerous flavonoids can inhibit vitamin C and DHA uptake by their respective transporters. The flavonoid quercetin can reversibly inhibit SVCT1 expressed in Xenopus oocytes [54] and restricted knowledge from an animal mannequin signifies that this will happen in vivo [54]. Quercetin and myricetin can inhibit the uptake of vitamin C and DHA into cultured monocytic (HL-60 and U937) and lymphocytic (Jurkat) cells through inhibition of GLUT1 and GLUT3 [55] and probably additionally SVCT2, which is expressed in leukocytes [56]. Quercetin and phloretin may also inhibit the intestinal GLUT2 and GLUT8 transporters [19]. Thus, primarily based on the above in vitro research, it’s unclear whether or not flavonoids will improve in vivo vitamin C bioavailability via a sparing motion, or lower its bioavailability via inhibiting vitamin C transporters.
The impact of assorted purified flavonoids or flavonoid-rich vegatables and fruits on vitamin C bioavailability in several animal fashions and human topics is mentioned beneath. To check comparative vitamin C bioavailability, each steady-state and pharmacokinetic fashions have been used. The previous displays ascorbate ranges in blood and/or urine following numerous weeks of supplementation, whereas the latter displays transient modifications in plasma ranges and/or urinary excretion over the hours following ingestion of the vitamin C-containing check substance. The gold customary for evaluation of vitamin C is HPLC with coulometric electrochemical detection as a result of its sensitivity and specificity [57]. Early research, nevertheless, have been restricted primarily to colourimetric strategies primarily based on discount of ferric iron compounds and are susceptible to interference by quite a few different substances [57].
2. Vitamin C Bioavailability Research Utilizing Animal Fashions
There are an a variety of benefits to using animal fashions to research vitamin C bioavailability, significantly the convenience of weight-reduction plan management and the power to acquire tissues not usually accessible in human research. Nonetheless, outcomes can fluctuate broadly relying on the animal mannequin used and the totally different remedy and analytical methodologies employed. It also needs to be famous that not all the animal fashions which have been used are naturally vitamin C poor. The animal fashions of selection are the naturally vitamin C poor guinea pig, and genetically scorbutic animal fashions, such because the Osteogenic Dysfunction Shionogi (ODS) rat [58], the l-gulono-γ-lactone oxidase (Gulo−/−) knockout mouse [59], and the spontaneous bone fracture (sfx) mouse [60]. Though animal research can present helpful data, translation of the findings to people ought to all the time proceed with warning.
Research investigating the comparative bioavailability of artificial versus pure vitamin C in animal fashions are proven in Desk 1. Research carried out in guinea pigs confirmed enhanced uptake of vitamin C into particular organs (e.g., adrenals and spleen) within the presence of flavonoid-rich juices/extracts or purified plant flavonoids (e.g., hesperidin, rutin, and catechin) [42,61,62,63,64]. Vinson and Bose [65] carried out a pharmacokinetic research in guinea pigs and located a 148% improve within the space beneath the plasma ascorbate concentration-time curve when administered as citrus fruit media. Additionally they famous that the citrus fruit group demonstrated delayed plasma vitamin C uptake in contrast with the artificial vitamin C group [65]. Cotereau et al. [42] reported that animals given each vitmain C and catechin not solely had 4 to eight-fold extra vitamin C within the organs measured, however they have been additionally the one group with out scorbutic-type lesions. The latter discovering was supported by an analogous research displaying fewer recent hemorrhages in scorbutic guinea pigs receiving vitamin C with rutin or querceitin in contrast with vitamin C alone [66].
A number of of the research in Desk 1, nevertheless, confirmed no variations in vitamin C accumulation in some organs (e.g., liver) [61,62,63,67]. Hughes et al. famous that the acerola cherry preparation they used was just about flavonoid free as a result of dilution of the excessive vitamin C fruit extract, which they instructed could have accounted for its decreased efficacy in contrast with blackcurrant juice, which is flavonoid wealthy [64]. To account for the flavonoid-dependent variations in vitamin C uptake noticed between the adrenals and livers of guinea pigs [62,63], Douglass and Kamp [62] famous that flavonols similar to rutin are quickly destroyed in liver tissue, however are comparatively steady in adrenal homogenates. Papageorge et al. [63] additionally famous that when epinephrine oxidizes it will probably contribute to the destruction of vitamin C and thus the antioxidant results of rutin could end in “sparing” of vitamin C in adrenals. A research by Levine’s group [54] confirmed that the flavonoid quercetin can reversibly inhibit vitamin C intestinal transport and reduce plasma ranges of the vitamin within the CD (Sprague-Dawley) rat, though it needs to be famous that this isn’t a vitamin C poor animal mannequin. A number of the variability noticed in these totally different animal research (Desk 1) could also be as a result of various ratios of flavonoid to vitamin C employed.
We lately carried out a comparative bioavailability research, utilizing the Gulo mouse mannequin, investigating the uptake of vitamin C from kiwifruit gel in contrast with artificial vitamin C [68]. We discovered that the kiwifruit extract, which is wealthy in flavonoids [69,70], offered considerably larger serum, leukocyte, coronary heart, liver, and kidney ranges of vitamin C than the purified vitamin, suggesting some sort of synergistic exercise of the entire fruit on this mannequin. As with Wilson et al. [61], we didn’t observe any distinction between the 2 interventions with respect to vitamin C uptake into the mind. Certainly, there’s important retention of vitamin C within the mind throughout dietary depletion [64,68], suggesting an important function for vitamin C within the mind. Thus, a major proportion of animal research present enhanced circulating and organ ranges of vitamin C within the presence of food-derived or purified flavonoids.
3. Regular State Bioavailability Research in People
An early report of a number of sufferers with scurvy whose plasma vitamin C ranges didn’t improve with artificial vitamin C alone, however solely within the type of lemon juice [45], initially leant assist to the “vitamin P”/flavonoid idea. Nonetheless, in distinction to the animal research, all regular state human research (summarized in Desk 2) have proven little distinction in plasma and/or urine bioavailability between artificial vitamin C and that from totally different fruits, fruit juices, and greens [35,71,72,73,74,75,76]. Mangels et al. [35] did observe a 20% decrease plasma bioavailability of vitamin C from uncooked broccoli in contrast with cooked broccoli, nevertheless, this will have been as a result of variations in mechanical homogenization (chewing), an analogous impact to that noticed for carotenoid absorption from uncooked versus cooked carrots.
We lately carried out a gentle state bioavailability research in younger non-smoking males supplemented for six weeks with 50 mg/day vitamin C, within the type of a chewable vitamin C pill or half a gold kiwifruit [77]. This dose was chosen because it lies on the steep a part of the sigmoidal plasma uptake curve [78], thus enhancing the chance of detecting a distinction between the 2 interventions. Though most regular state research have used sequential or crossover research designs, we selected a randomized parallel arms design for numerous causes. Block et al. [79] have beforehand noticed a decrease plasma vitamin C response to supplemental vitamin C within the second part of a a number of depletion/repletion research. Moreover, though washout of vitamin C could possibly be monitored between the 2 phases of a cross-over research, it could not be doable to watch washout of different kiwifruit-derived elements, e.g., vitamin E, which can have an effect on the second part of a cross-over research as a result of potential in vivo interactions with the supplemental vitamin C [30].
Just one earlier research has investigated the comparative bioavailability of artificial versus pure vitamin C in leukocytes [71]. These investigators discovered no distinction in leukocyte vitamin C uptake between artificial vitamin C (within the presence or absence of rutin) and that in orange juice two hours after a single 75 mg dose [71]. Subsequently, along with plasma, urine, and semen samples, we additionally remoted peripheral blood mononuclear cells and neutrophils earlier than and after intervention. As a result of ease of accessibility and isolation, peripheral blood leukocytes are sometimes used as a marker for tissue vitamin C standing, nevertheless, whether or not they’re a very good mannequin for all organs and tissues is unsure. In assist of this premise our animal research indicated that totally different organs exhibited maximal vitamin C uptake at various doses of the vitamin [68] and we’ve got lately proven that human skeletal muscle reveals better relative uptake of vitamin C than leukocytes [80]. Subsequently, we additionally carried out needle biopsies of skeletal muscle tissue (vastus lateralis), earlier than and after intervention. In distinction to our earlier animal research [68], our human research clearly confirmed no variations within the steady-state bioavailability of kiwifruit-derived versus artificial vitamin C to plasma, semen, peripheral blood leukocytes, and skeletal muscle tissue [77]. Thus, different vitamins and phytochemicals current in kiwifruit are neither enhancing nor inhibiting the uptake of vitamin C from the entire fruit in people.
4. Pharmacokinetic Bioavailability Research in People – “vitamin c natural form”
Pharmacokinetic research present transient modifications in plasma vitamin C ranges and urinary excretion over the hours following ingestion of the vitamin C-containing check substance (related research are proven in Desk 3). Supplemental vitamin C sometimes takes about two hours to achieve maximal plasma ranges following ingestion. An early animal research discovered that vitamin C offered in citrus fruit media took longer to achieve peak plasma concentrations in contrast with an artificial vitamin C resolution and likewise offered a bigger space beneath the plasma vitamin C concentration-time curve [65]. These similar investigators noticed a comparable pattern in human topics supplemented with 500 mg vitamin C within the presence or absence of a citrus fruit extract [81]. The citrus fruit extract delayed maximal plasma ranges by one hour and offered a 35% improve in vitamin C bioavailability. Apparently, the citrus fruit extract elevated 24 h urinary vitamin C excretion in members pre-saturated with vitamin C, however decreased excretion in non-saturated members in contrast with artificial vitamin C alone. This means that the baseline vitamin C standing of the person could have an effect on the comparative bioavailability of vitamin C. Though two different research confirmed elevated urinary excretion in vitamin C pre-saturated topics within the presence of fruit juice [71,82], one other pre-saturation research confirmed comparable plasma ranges and 24 h urinary excretion within the presence of blended bioflavonoids [83]. It needs to be famous that doses of 500 mg vitamin C have decreased intestinal bioavailability [78] and are considerably larger than could be obtained via a standard every day weight-reduction plan.
A variety of pharmacokinetic research have proven comparable bioavailability of vitamin C equipped in artificial kind or within the presence of meals or fruit juices [84,85,86,87,88]. Nelson et al. [88] used an intestinal triple lumen tube perfusion mannequin to research the absorption of artificial vitamin C and that from an orange juice resolution. This methodology permits direct measurement of intraluminal occasions and confirmed no distinction within the absorption of vitamin C from the 2 check options. A number of pharmacokinetic research have proven transient decreases in plasma vitamin C ranges and/or urinary excretion at particular time factors within the presence of meals and fruit juices [34,71,84,85]. The physiological relevance of those transient variations is, nevertheless, possible minimal.
We lately carried out a pharmacokinetic bioavailability research of artificial versus kiwifruit-derived vitamin C in 9 non-smoking males (aged 18–35 years) who had “healthy” or “optimal” (i.e., >50 μmol/L) baseline ranges of plasma vitamin C [89]. The members acquired both a chewable pill (200 mg vitamin C) or the equal dose from gold kiwifruit. Fasting blood and urine have been collected half hourly to hourly over the eight hours following intervention. Plasma ascorbate ranges elevated from 0.5 h submit intervention, though no important variations within the plasma time-concentration curves have been noticed between the 2 interventions. An estimate of the overall improve in plasma ascorbate indicated full uptake of the ingested vitamin C pill and kiwifruit-derived vitamin C. There was a rise in urinary ascorbate excretion, relative to urinary creatinine, from two hours submit intervention. There was additionally a major distinction between the 2 interventions, with enhanced ascorbate excretion noticed within the kiwifruit group. Urinary excretion was calculated as ~40% and ~50% of the ingested dose from the vitamin C pill and kiwifruit arms, respectively. Total, our pharmacokinetic research confirmed comparable relative bioavailability of kiwifruit-derived vitamin C and artificial vitamin C [89].
5. Vitamin C Bioavailability from Totally different Pill Formulations
Doses of vitamin C as much as 2000 mg/day are thought-about secure for normal consumption [90]. Nonetheless, pharmacokinetic research point out that ingestion of single doses of vitamin C better than 200 mg have decrease relative bioavailability [78], indicating that ingestion of a number of smaller doses every day is preferable to a single giant dose. A variety of research have investigated the relative bioavailability of vitamin C from totally different pill formulations and have proven that slow-release formulations present superior vitamin bioavailability [91,92,93,94]. Salts of vitamin C, similar to sodium and calcium ascorbate (Ester-C), have additionally been examined. Animal research indicated that Ester-C (which comprises calcium ascorbate, in addition to DHA and calcium threonate) was absorbed extra readily and excreted much less quickly than ascorbic acid [95] and had superior anti-scorbutic exercise in ODS rats [96]. Johnston and Luo [83], nevertheless, discovered no important variations between Ester-C and ascorbic acid bioavailability in people. However, Ester-C has been proven to be higher tolerated in people delicate to acidic meals [97].
6. Conclusions
Total, a majority of animal research have proven variations within the comparative bioavailability of artificial versus food-derived vitamin C, or vitamin C within the presence of remoted bioflavonoids, though the outcomes diversified relying on the animal mannequin, research design and physique compartments measured. In distinction, all regular state comparative bioavailability research in people have proven no variations between artificial and pure vitamin C, whatever the topic inhabitants, research design or intervention used. Some pharmacokinetic research in people have proven transient and small comparative variations between artificial and pure vitamin C, though these variations are more likely to have minimal physiological affect. Thus, not solely do the reviewed research reiterate the injunction that the findings of animal research shouldn’t be instantly translated to people [98,99], however additionally it is obvious that extra comparative bioavailability research in people are unwarranted.
Though artificial and food-derived vitamin C look like equally bioavailable in people, ingesting vitamin C as half of an entire meals is taken into account preferable due to the concomitant consumption of quite a few different macro- and micronutrients and phytochemicals, which can confer extra well being advantages. Quite a few epidemiological research have indicated that larger intakes of fruit and greens are related to decreased incidence of stroke [100], coronary coronary heart illness [101], and cancers at numerous websites [102,103]. Vitamin C standing is without doubt one of the finest markers for fruit and vegetable consumption [104], and food-derived vitamin C is related to decreased incidence of quite a few continual illnesses [1], nevertheless, whether or not the noticed well being results of fruit and vegetable ingestion are as a result of vitamin C and/or different plant-derived elements is presently unknown. With respect to coronary coronary heart illness, sturdy proof exists for a protecting impact of greens, reasonable proof for fruit and dietary vitamin C and inadequate proof for supplemental vitamin C [105]. Some meta-analyses assist the premise that dietary vitamin C is extra protecting than dietary supplements [106], whereas others present decreased illness incidence with supplemental however not dietary vitamin C [107].
A serious limitation with epidemiological research is that they present solely an affiliation between dietary vitamin C consumption and illness threat and can’t verify whether or not totally different sources of vitamin C (i.e., food-derived versus complement) are a trigger, consequence, or just a correlate of the actual end-point measured. Interpretations may also fluctuate considerably relying on the enter of various confounders [108]. Moreover, epidemiological research rely predominantly on meals frequency questionnaires [109,110] and 24 h dietary remembers [111] to determine vitamin C intakes from meals and/or dietary supplements [112]. This system has quite a few limitations [113] and correlations with vitamin C standing can fluctuate relying on the strategies employed in addition to quite a few different exterior components [114]. Pooled or meta-analyses of epidemiological research are significantly problematic as a result of combining of variable research designs, cohorts and endpoints, usually leading to dilution or misinterpretation of research findings.
The gold customary for figuring out causality is the double-blind randomized placebo managed scientific trial. Though this kind of research design works properly for evaluating the results of medicine towards a placebo, it doesn’t work for vitamins, similar to vitamin C, that are already within the meals chain and are required for all times, i.e., there isn’t a true placebo. Quite a few different methodological points have been recognized with the design of many scientific trials investigating the well being results of vitamin C [115]. For instance, a significant flaw with many vitamin C intervention research is using research populations with already enough and even saturating vitamin C ranges, which considerably decreases the chance of observing any results of the intervention. Thus, it is suggested that research populations are comprised of people with sub-optimal vitamin C standing (i.e., <50 μmol/L plasma vitamin C) or that sub-group evaluation is carried out on the low vitamin C sub-populations [116]. With pharmacokinetic research, each unsaturated and saturated people can be utilized, however comparative bioavailability research have proven that outcomes could fluctuate relying on the baseline vitamin C standing of the research topics. Moreover, the vitamin C doses chosen for intervention are important since doses above 200 mg have decreased intestinal uptake [78], indicating that if larger doses are warranted then these needs to be offered as a number of doses of ~200 mg every to make sure full bioavailability. The comparative well being results of supplemental versus food-derived vitamin C will solely be decided via using applicable and well-designed research. Dedication of the physiological results or well being outcomes of intervention with artificial versus pure vitamin C will rely largely on the endpoints measured. Solely a handful of comparative intervention research have been carried out to evaluate particular physiological or well being endpoints. Guarnieri et al. [89] investigated potential safety of mononuclear leukocytes from supplemented people towards ex vivo oxidative DNA injury. Though they discovered comparable vitamin C bioavailability between a single portion of orange juice (containing 150 mg vitamin C) and an artificial vitamin C drink of the identical dosage, they confirmed that solely the orange juice protected the leukocytes from ex vivo oxidative DNA injury [89]. Nonetheless, how intently ex vivo oxidation of DNA resembles occasions occurring in vivo is debatable and outcomes might additionally fluctuate considerably relying on the kind of oxidative stress. Johnston et al. [76] in contrast plasma lipid peroxidation in people who had been supplemented with both orange juice or artificial vitamin C (~70 mg/day) for 2 weeks. They discovered comparable vitamin C bioavailability and an analogous discount in lipid peroxidation with each interventions [76]. A number of research have assessed the results of artificial and pure vitamin C, or vitamin C within the presence of bioflavonoids, on the frequent chilly. Two earlier research confirmed an absence of an impact of vitamin C (~200 mg/day), with and with out purified bioflavonoids, on the prevention and remedy of the frequent chilly [117,118]. One other research indicated that artificial vitamin C (80 mg/day) and orange juice each decreased the signs of the frequent chilly in contrast with placebo, however there have been no variations between the 2 interventions [119]. As alluded to within the introduction, vitamin C is understood to boost the bioavailability of different vitamins, similar to vitamin E [30] and non-heme iron [31,32], which can improve the well being results of vitamin C-containing meals. Bioflavonoids are additionally identified to have quite a few organic actions [120]. Not too long ago vitamin C has been proven to modulate particular organic actions of quercetin and tea polyphenols [121,122]. Thus, future research could elucidate the physiological relevance of those interactions.
“vitamin c natural form”