Available online at www.sciencedirect.com Nutrients and phytochemicals: from bioavailability to bioefficacy beyond antioxidants Birgit Holst1 and Gary Williamson1,2 The effect of any dietary compound is influenced by the active certain lipids and carbohydrates. As the latter is caused bioavailable dose rather than the dose ingested. Depending on by socio-economical factors rather than by a lack of the individual predisposition, including genetics and scientific knowledge, modern nutrition research has medication, a bioavailable dose may cause different changed focus. Traditionally, defining nutrient require- magnitudes of effects in different people. Age might affect the ments, identifying and correcting nutrient deficiencies, predisposition and thus the requirements for nutrients including and chemical and microbial contamination-related food phytonutrients (e.g. phytochemicals such as flavonoids, safety issues received most attention. Current emphasis is phenolic acids and glucosinolates). These are not essential for directed towards the development of functional, health growth and development but to maintain body functions and promoting foods and dietary recommendations for health health throughout the adult and later phases of life; they are maintenance and well-being throughout life, as well as ‘lifespan essentials’. Major mechanisms involved in chronic, diets for special groups of the population. On that basis, age-related diseases include the oxidant/antioxidant balance, significant research effort is focused on minor dietary but the latest research indicates indirect effects of dietary constituents, vitamins and trace elements, phytochem- bioactives in vivo and adaptive responses in addition to direct icals (carotenoids, flavonoids, indoles, isothiocyanates, radical scavenging. and so on), zoochemicals (conjugated linoleic and n À 3 Addresses fatty acids, and so on), fungochemicals and bacteriochem- 1 BioAnalytical Science Department, Nestle´ Research Center, Nestec icals (formed during food fermentations and by the gut Ltd., Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland microflora). 2 Chair of Functional Food, Procter Department of Food Science, University of Leeds, Leeds LS2 9JT, UK Vitamins have been known for a long time to be essential Corresponding author: Holst, Birgit ([email protected]) for our body, and, during evolution, humans have lost the capacity to synthesize these compounds. They are specifically taken up, transported, metabolized and Current Opinion in Biotechnology 2008, 19:73–82 excreted depending on body requirements. Selected This review comes from a themed issue on vitamins have been proposed and intensively studied Food Biotechnology as being responsible for the health benefits assigned to Edited by Hannelore Daniel and Martin Kussmann fruits and vegetables. Available online 9th April 2008 Today, new functions of well-known micronutrients are 0958-1669/$ – see front matter studied as well as traditional ethnic plant foods, herbal # 2008 Elsevier Ltd. All rights reserved. extracts but also well-known and commonly consumed DOI 10.1016/j.copbio.2008.03.003 fruits and vegetables containing less well characterized active components designated as phytochemicals or phy- tonutrients. Introduction As early as in the first weeks of life but especially Among the well-known micronutrients, selenium and throughout adulthood and in the elderly populations, vitamin E are currently of interest for a range of func- our diet has a significant impact on health and well-being. tionalities beyond their vitamin function. One example is Examples range from neural tube defects caused by folate the increased viral pathogenicity and virulence of benign deficiencies in the unborn to age-related, chronic diseases viruses in deficiency conditions of these micronutrients, such as diabetes, cancer, cardiovascular and Alzheimer’s which may be related to an increased mutation rate in the disease. For diabetes, the metabolic syndrome and clini- virus population [1]. cally manifested deficiencies, an unbalanced nutrition or an inadequate diet are already established as key risk Although not designated as vitamins, there is a large group factors. On the basis of well-defined macronutrient and of compounds in fruits and vegetables, teas and herbal mineral requirements, possible interventions are known extracts which might not be essential throughout life or by scientists, authorities and the general population. cause clinically manifested deficiencies, but are essential Nevertheless, a large proportion of the world population for health and well-being in adulthood and in the elderly still suffers from severe deficiencies of major nutrient population. These compounds – phytochemicals – are groups while other populations are affected by diseases plant secondary metabolites, which protect the plant related to an over-consumption of nutrients such as against a variety of stresses. When consumed with the diet, www.sciencedirect.com Current Opinion in Biotechnology 2008, 19:73–82 74 Food Biotechnology they may reduce the risk of age-related chronic diseases. This review discusses mainly phytochemicals as these are a Examples of classes of phytochemicals include flavonoids, major focus of current functional food development. phenolic acids, glucosinolate-derived compounds such as Furthermore, their uptake into the body and bioavailability isothiocyanates, terpenes, and low-molecular weight can be much lower than the bioavailability of ‘classical sulphur-containing compounds. nutrients’ but critical for their biological effects. Key lessons from the vitamins and trace elements will be Many of the phytochemicals and some vitamins have utilized to guide future research on phytochemicals. antioxidant activity in vitro, which has led to the use of the general term ‘antioxidants’. These have been linked What is bioavailability? to the health benefits of fruit and vegetables but too much On oral consumption, the uptake of micronutrients and of a ‘good’ thing can be bad, as shown from data examin- phytochemicals into the body is not complete, and a certain ing the effects of high doses of antioxidants individually percentage is not absorbed. To quantify the amount that is or in combination: results have been disappointing, even actually absorbed, distributed to the tissue, metabolized alarming. Thus, recent meta-analyses concluded that and eventually excreted, the term bioavailability was high, pharmacological doses of individual antioxidant introduced. Bioavailability describes the concentration of vitamins exert no health benefits, and might even a given compound or its metabolite at the target organ; increase the risk for certain diseases in some groups of however, no single definition exists that accurately takes the population [2,3]. into account the multi-factorial nature of the term. The Food and Drug Administration defines bioavailability as What went wrong, since these studies were designed to ‘the rate and extent to which the therapeutic moiety is absorbed show a positive effect on health? The apparent contro- and becomes available to the site of drug action’. Because of versy can be related to the high doses used, and thus difficulties in accessing organ sites in vivo in humans, closely to the bioavailability of antioxidants. Most effects attempts to use the term with quantitative precision or of micronutrients in general and dietary antioxidants in to calculate exact values in humans are challenging. As particular follow a U-shaped curve (Figure 1), with low or a consequence, the term ‘absolute bioavailability’is deficiency levels causing an increased disease risk, an often used by clinical pharmacologists to describe the optimal, protective amount (which may be a narrow or exact amount of a compound that reaches the systemic broad range), and excessive levels causing again an circulation, calculated as the fraction of the area under the increased disease risk. curve (AUC) after oral ingestion compared with the AUC after intravenous administration. In nutrition, however, Figure 1 ‘relative bioavailability’ is commonly used to describe the bioavailability of a compound from one source compared with another. The ‘classical’, pharmacological definition of bioavailability covers several linked and integrated processes; specifically, liberation, absorption, distribution, metabolism and excretion (generally presented under the acronym LADME, Figure 2). L = Liberation, processes involved in the release of a compound from its matrix. A = Absorption, the diffusion or transport of a compound from the site of administration into the systemic circulation. D = Distribution, the diffusion or transportation of a compound from the intravascular (systemic circulation) to the extra-vascular space (body tissues). M = Metabolism, the biochemical conversion or biotransformation of a compound. E = Excretion, the elimination of a compound, or its metabolite, from the body via renal-, biliary- or pulmonary processes. Many factors affect the bioavailability of a compound; Theoretical risk of chronic disease with dietary deficiency or excess these may be divided into exogenous factors such as the (‘mega-dose’). The dose–response of nutrients in general and complexity of the food matrix, the chemical form of phytochemicals in particular is not linear. At low concentrations deficiencies may be observed. Following a physiological dose range, the compound of interest, structure and amount of which can be relatively narrow, a further increase of the dose may lead