Dr Derek H Shrimpton, scientific advisor to the European Federation of Health Product Manufacturers (EHPM) considers the nutritional implications of micronutrient interactions
This review is focused on those vitamins, minerals and trace elements that are most usually associated with nutritional supplements. It is primarily concerned with their capacity to interact with each other once they have been swallowed.
Four types of interaction are considered:
Chemical - some of which may also take place before consumption, during the manufacture of the nutritional supplements.
Biochemical - in which there may be competition between micronutrients for a common site of absorption and/or transport; where an antioxidant cycle may be facilitated; and where a biochemical sequence may be involved with a health benefit.
Physiological - which may result in either increased or decreased utilisation.
Clinical - where a marker for improved health may be involved or where a nutritional deficiency may be masked.
These interactions are most likely to be of nutritional significance for those individuals whose consumption of vitamins, minerals and trace elements is at or below the RDA and whose preferred potency for nutritional supplements is at the RDA.
Currently in the UK the majority of sales of nutritional supplements of vitamins, minerals and trace elements are formulated at RDA level.2 Furthermore, there are sections of the population whose daily intake does not reach the RDA for many vitamins and trace elements.3 Amongst these are those on slimming diets and those aged over 65 years.4
The evidence for the interactions reported below has been obtained from biological studies; but it is also possible that suitable conditions for these reactions could occur in microclimates within portions of tablets and capsules during manufacture and subsequent distribution and storage during the commonly declared shelf life of the nutritional supplement.
Copper, in the presence of inorganic sulphate at high concentrations, up to 4,000ppm, forms an insoluble thiomolybdate and may thus reduce the amount of molybdenum that is absorbed and retained in the body.5 Phosphorus can form an insoluble magnesium-calcium-phosphate complex and consequently decrease the absorption of magnesium.6
Zinc may form insoluble complexes with folic acid, particularly at low pH.7 If these complexes have been formed in the stomach, they should dissolve at the higher pH within the duodenum, but if they have been formed before consumption, then they will not be absorbed from the intestinal tract and will be voided.
Vitamin B2 (riboflavin) forms an advantageous complex with zinc, resulting in its increased absorption.*
Folic acid (B9) forms a different complex with zinc oxide which is insoluble at the higher pH of the duodenum, resulting in its decreased absorption.9
Vitamin C (ascorbic acid) is able to reduce selenite to elemental selenium, which is biologically inert, if no other nutrients are present.10 Vitamin B12 is destroyed if it is administered orally as a drug with ascorbic acid."
Neither reaction is likely to occur in multi-vitamin-mineral-trace element preparations unless iron is also present, when it has been reported, in a study in which cyanocobalamin was present with its analogues, that up to 30 per cent of the activity of the vitamin B12 may be lost.12
The B vitamins are essential co-factors in many metabolic reactions and consequently relate indirectly one to another. For example, vitamins B3 and B6 are functional components of enzymes involved in the release of energy from food and to this extent they interact indirectly with each other; but neither enhances or depresses the activity of the other.
The biochemical interactions are considered in three groups:
* competition for a common site of absorption
* facilitation of a biochemical sequence
* facilitation of an antioxidant cycle.
Competition for a common site of absorption
There is a complex situation with trace elements close to each other in the periodic table where it is thought that they may share a common uptake mechanism in the gut and may be competing for the binding ligands that mediate intestinal absorption and subsequent transport into the blood." This group includes chromium, cobalt, copper, iron, manganese and zinc and also the toxic metals cadmium and lead. It is speculated that deficiency of one or more of this group may result in antagonistic competition for absorption, resulting in a deficiency of one or more of the essential trace elements leading to a predisposition to the toxic effects of cadmium and lead.
Calcium has an inhibitory effect on absorption of iron provided that the two elements are consumed at the same time.14 Calcium also depresses the absorption of zinc.15 Chromium interacts with iron in binding to transferrin and consequently can impair iron metabolism and storage."
Copper and zinc are mutually antagonistic, a dietary excess of one depressing the absorption of the other; but the amounts necessary to demonstrate this effect are substantially greater than any that are likely to occur in conventional diets."
Iron and zinc have been reported to interfere with the absorption of each other, although the mechanism of the antagonism is not clear." Iron in the presence of ascorbic acid (vitamin C) and in relatively high amounts depresses the absorption of copper."
Manganese can depress the absorption of iron by as much as 40 per cent, although the amount may vary depending on the nutrients present and the form of the iron.™ For example, it could be anticipated that there would be no comparable effect on the haem iron of meat.
Riboflavin (vitamin B2) is necessary for the absorption of iron, which is depressed when dietary riboflavin is deficient.21
Biotin and pantothenic acid share a common carrier mediated uptake system, but no nutritional implications have been identified.22
Vitamin C appears to have a direct interaction with iron, resulting in its increased absorption provided the two micronutrients are consumed together.13
Vitamin A may indirectly aid the absorption of iron by preventing the inhibitory effects of phytate.23 Vitamin A can, when present in large amounts, interfere with the absorption of vitamin K and rats this has been accompanied by haemorrhages.24
Vitamin D regulates the absorption of calcium and this may be the result of the action of the vitamin on the transport of calcium from the lumen of the gut.25
It has been concluded from animal studies that vitamins A and D may lessen the toxic effect of each other and it has been suggested that this may be as a result of a mutual antagonistic interaction.26
Vitamin E when consumed with vitamin A in relatively large amounts (SOOmg E and 60mg A) can increase the absorption of vitamin A and may also reduce its toxicity.27, 28
Where nutritional recommendations are quoted, the term RDA (recommended daily allowance)has been used referring to the "Labelling RDA" as required by current EU law. This has the advantage for the consumer of providing a single reference point in place of separate RNIs (reference nutrient intake) for male and female and for different age ranges.
Facilitation of a biochemical sequence
Vitamin B12 is a necessary component of the enzyme system involved in the conversion of folates to their metabolically active form. The essential step in the sequence is suppressed when vitamin B12 is deficient.29
Vitamin K may be an essential component in the sequence of reactions which enables calcium ions to be bound to prothrombin and which in turn can then be bound to phospholipids and activated to thrombin.30 The blood clotting mechanism centred on thrombin is then in place.
Facilitation of an antioxidant cycle
Vitamin C has been implicated in a hypothetical cyclic regeneration of vitamin E in which vitamin C acts as a reducing agent.31 Although the concept of sparing vitamin E by regenerating its activity is attractive, there is insufficient evidence to support the possibility that the hypothesis is nutritionally significant.
For the purpose of this discussion, physiological interactions are confined to those affecting utilisation, either reduced or increased.
Interactions which increase utilisation
Vitamin bi (thiamin) has been shown to increase the utilisation of pantothenic acid.32
Vitamin B2 (riboflavin) has also been shown in the same trial to increase the utilisation of pantothenic acid, but to a lesser degree than vitamin B.32
The utilisation of iron has been shown to be increased when riboflavin deficient diets were supplemented with riboflavin, but there is no reported benefit on the utilisation of iron from the consumption of riboflavin in amounts that exceed the RDA.21
Vitamin B12 has been shown, in chicks, to improve the utilisation of pantothenic acid.33
Pantothenic acid appears, from studies with rats, to improve the efficiency of utilisation of vitamin C (ascorbic acid).34 Vitamin A directly affects the transport of iron and the production of red cells. It is also possible that when vitamin A is deficient, the mobilisation of iron from body stores is also impeded.23
Vitamin C influences the storage and transport of iron, possibly by involvement in the modulation of ferritin synthesis and consequently in the efficiency of utilisation of iron.35•" Vitamin D regulates calcium and phosphate metabolism and the efficiency of their utilisation. Vitamin D is active in many tissues, the main ones being the intestine, bone and kidney where reabsorption of calcium is an important contribution to the overall economy of calcium.37
Vitamin K is involved in the utilisation of calcium in the early stages of the formation of bone tissues.38 The process of bone formation and renewal is complex, involving not only vitamins D and K, but also osteocalcin and possibly other protein regulators. In addition, magnesium is intimately involved through its participation in the release of parathyroid hormone. Consequently it is necessary to consider vitamins D and K and the minerals which form bone as one complex entity, recognising that there may be other compounds capable of influencing the system.
Interactions which reduce utilisation
Folic acid has been reported to lower serum levels of vitamin B12 and also of zinc, but others have failed to repeat the observations.39 40 At present there is insufficient evidence to support the conclusion that there could be an interaction between folate and either vitamin B12 or zinc which could result in reduced utilisation.
Vitamin C has been mistakenly associated with a reduction in the absorption of copper from the small intestine.41 The most probable explanation of the observed decreased copper activity is that ascorbic acid promotes the dissociation of copper from ceruloplasmin and consequently lowers its oxidase activity.42
Vitamin E has no measurable effect on clotting time and hence no quantifiable interaction with vitamin K when present in the diet at RDA levels. Conversely, when vitamin E is added to the daily diet in supplements containing more than 250mg there is an effect on clotting time.43 It has been suggested that this might result from interference by vitamin E with the carboxylation reaction needed to activate vitamin K dependent clotting factors.44
Copper has been associated with reduced activity of pantothenic acid in studies with chicks.45Interaction with molybdenum is also known to occur, probably in the circulatory system, but has not been observed in humans.46
Selenium is involved in iodine metabolism and although an excess of selenium will not increase the efficiency of iodine utilisation, a deficiency will impair its utilisation.47
The following reactions are those which have a clinically demonstrable consequence. They are thus of direct relevance to human nutrition.
Folic acid in combination with vitamin B[2 and vitamin B6 is involved in the metabolism of homocysteine to cysteine and methionine. Provided the vitamins are present together and in adequate amounts, homocysteine is converted to cysteine and methionine and its concentration in blood remains low.48 Associated with low blood concentrations of homocysteine is a lowered risk of coronary disease.49 While the metabolic processes are well understood, the reason why homocysteine should be a marker for coronary disease is not.
Folic acid can mask vitamin B12 anaemias when provided as a supplement in daily amounts of 5mg.50 This does not occur when the daily supplement is 1 mg or less. This effect has not been included in the summary of interactions because daily supplementation in excess of 1 mg/day is not recommended in either North America or Europe except under medical control.
The micronutrient interactions which have been reviewed in the preceding sections are summarised in the table. Quantitative data is not given because in many instances there is insufficient data from which to make firm quantitative conclusions. Where this is possible it is stated in the text.
In most of the instances cited the concentrations and daily intakes of the micronutrients have been at physiological levels, that is at or about the RDA. Where this has not been so it has been stated.
The interactions that have been documented are nutritionally significant for the formulation of nutritional supplements in the UK where more than 90 per cent of sales in 1998 and 1999 were as multivitamin-mineral products in which the constituents were present at or about the RDA.
It is unlikely that the consumer of multivitamin-mineral supplements will be placed at risk by failure to recognise the known interactions between micronutrients, but the claimed benefits may not be fully realised in those instances where the possibility of micronutrient interaction has been ignored. ©
References available on request. Also published on www.dotpharmacy.com
A positive and potentially beneficial interaction
A negative and potentially disadvantageous interaction
Conflicting data with ambiguous nutritional implications.
Vitamin B3 is not included in the matrix because it is not associated with interactions of nutritional significance.
Manganese is not included in the matrix because its only reported interaction is with iron, whose absorption it can depress.
Vitamin C does not react with selenium but with selenite, oxidising it to selenium which cannot be absorbed from the gut.