nutrients Review Natural Sources, Pharmacokinetics, Biological Activities and Health Benefits of Hydroxycinnamic Acids and Their Metabolites Matej Sova 1,* and Luciano Saso 2 1 Faculty of Pharmacy, University of Ljubljana, Aškerˇceva7, 1000 Ljubljana, Slovenia 2 Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; [email protected] * Correspondence: matej.sova@ffa.uni-lj.si; Tel.: +386-1-476-9556 Received: 24 June 2020; Accepted: 22 July 2020; Published: 23 July 2020 Abstract: Hydroxycinnamic acids (HCAs) are important natural phenolic compounds present in high concentrations in fruits, vegetables, cereals, coffee, tea and wine. Many health beneficial effects have been acknowledged in food products rich in HCAs; however, food processing, dietary intake, bioaccessibility and pharmacokinetics have a high impact on HCAs to reach the target tissue in order to exert their biological activities. In particular, metabolism is of high importance since HCAs’ metabolites could either lose the activity or be even more potent compared to the parent compounds. In this review, natural sources and pharmacokinetic properties of HCAs and their esters are presented and discussed. The main focus is on their metabolism along with biological activities and health benefits. Special emphasis is given on specific effects of HCAs’ metabolites in comparison with their parent compounds. Keywords: diet; natural compounds; phenolic acids; hydroxycinnamic acids; metabolites; pharmacokinetic properties; biological activities; health effects 1. Introduction Our diet rich in plant food contains several health-beneficial ingredients. Among such ingredients, polyphenols represent one of the most important natural compounds. Phenolic compounds are members of probably the largest group of plant secondary metabolites and have the main function to protect the plants against ultraviolet radiation or invasion by pathogens [1,2]. They can be divided into four distinct classes based on the number of phenol rings and structural fragments connecting them, namely phenolic acids, flavonoids, stilbenes and lignans [2]. The first class generally involves the phenolic compounds possessing a carboxylic acid as the main functional group [3], thus being named as phenolic acids, which are further split into two groups, namely hydroxybenzoic and hydroxycinnamic acids (HCAs) (Figure1). Hydroxybenzoic acids are important bioactive ingredients of edible plants [4–6]; however, more common and studied phenolic acids are HCAs, which are present in the variety of plant-based foods, especially in fruit, vegetables and seeds [3]. HCAs possess phenylpropanoid C6-C3 structure as the main chemical scaffold and are recognized by the presence of hydroxyl group(s) on the aromatic ring(s) and a carboxyl group in the lateral chain [7,8]. The number and position of hydroxyl groups and other substituents contribute to the diversity of HCAs. The most abundant HCAs in nature are para-coumaric, caffeic, ferulic, and sinapic acids (Figure1)[ 8,9]. In nature, all four acids are rarely present in a free form and are usually esterified with quinic and tartaric acids or various derivatives of carbohydrates [10]. Chlorogenic acids are one the most abundant esters including the whole set of HCAs esters with quinic acid, namely caffeoyl-, feruloyl-, dicaffeoyl- and Nutrients 2020, 12, 2190; doi:10.3390/nu12082190 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 2190 2 of 30 Nutrients 2020, 12, x FOR PEER REVIEW 2 of 31 coumaroylquinic acids [11,12]. The most common representative is 5-O-caffeoylquinic acid (Figure1) caffeoylquinicoften referred toacid as chlorogenic(Figure 1) often acid referred [12]. An to ester as chlorogenic of caffeic acid acid and [12]. 3,4-dihydroxyphenyllactic An ester of caffeic acid acidand 3,4-dihydroxyphenyllacticis called rosmarinic acid (Figure acid is1 called), which rosmarinic is one of ac theid most (Figure abundant 1), which ca isff oneeic acid of the ester most in abundant the plant caffeickingdom acid besides ester in chlorogenic the plant kingdom acids [13 ].besides chlorogenic acids [13]. CaffeicCaffeic acidacid presentspresents up up to to 70% 70% of of whole whole HCAs HCAs in fruits,in fruits, whereas whereas ferulic ferulic acid acid is the is prevalent the prevalent HCA HCAin cereal in cereal grains grains [10]. The [10]. daily The consumptiondaily consumption of HCAs of variesHCAs significantlyvaries significantly between between individuals individuals [14–16], which[14–16], is which attributed is attributed not only not to di onlyfferent to differen intake butt intake also diversebut also metabolism diverse metabolism and absorption and absorption from the fromgut. Thethe bioavailabilitygut. The bioavailability and metabolism and metabolism of HCAs and of theirHCAs conjugates and their is thusconjugates of high is importance thus of high for importancehealth benefits for forhealth particular benefits individual. for particular individual. Herein, wewe willwill briefly briefly present present natural natural sources sources and and pharmacokinetic pharmacokinetic properties properties of HCAs of HCAs and theirand theiresters. esters. Afterwards, Afterwards, the main the focusmain willfocus be will on theirbe on metabolism, their metabolism, biological biological activities activities and health and benefits health withbenefits emphasis with emphasis on specific on especificffects of effect HCAss of mediated HCAs mediated by their metabolites.by their metabolites. Hydroxybenzoic acids Phenolic acids Hydroxycinnamic acids (HCAs) O O O O HO H CO H3CO OH 3 OH OH OH HO HO HO HO OCH3 Caffeic acid Ferulic acid p-Coumaric acid Sinapic acid Esters of main HCAs O O HO HO OH OH O OH OH O O O HO HO H3CO O OH O OH O OH OH OH HO HO HO 5-O-Caffeoylquinic acid 5-O-Feruoylquinic acid Rosmarinic acid O OH O OH O OH O O O O HO OH HO H3CO O OH O OH O O HO OH OH HO HO O Caftaric acid Fertaric acid Coutaric acid FigureFigure 1. 1.Structure Structure ofof thethe mainmain hydroxycinnamic acids (HCAs) and and their their esters esters as as one one of of the the major major class of phenolic acids. class of phenolic acids. 2. Dietary Intake and Nutritional Importance of HCAs 2. Dietary Intake and Nutritional Importance of HCAs HCAs are one of the most widely distributed naturally occurring phenolic acids being typically HCAs are one of the most widely distributed naturally occurring phenolic acids being typically present in the form of esters with quinic, shikimic or tartaric acid, saccharides, flavonoids or with plant present in the form of esters with quinic, shikimic or tartaric acid, saccharides, flavonoids or with structural elements (i.e., cellulose, lignin and proteins) [12,17,18]. HCAs are considered as important plant structural elements (i.e., cellulose, lignin and proteins) [12,17,18]. HCAs are considered as constituents of our diet, contributing to taste, color, nutritional value and health benefits [14]. HCAs are important constituents of our diet, contributing to taste, color, nutritional value and health benefits thus present at a wide concentration range in our everyday food and drinks, including fruits (apples, [14]. HCAs are thus present at a wide concentration range in our everyday food and drinks, including berries, plums, cherries, peaches and some citrus fruits), vegetables (carrots, salad, cabbage, eggplant, fruits (apples, berries, plums, cherries, peaches and some citrus fruits), vegetables (carrots, salad, and artichoke), cereals, beverages (tea, coffee), grapes and wine [14,19–22]. HCA derivatives represent cabbage, eggplant, and artichoke), cereals, beverages (tea, coffee), grapes and wine [14,19–22]. HCA about 18% of all phenolic compounds in apples with chlorogenic acid as the most abundant HCA in derivatives represent about 18% of all phenolic compounds in apples with chlorogenic acid as the the entire apple (up to 87% of the total HCA amount) [23], whereas p-coumaric, caffeic and ferulic most abundant HCA in the entire apple (up to 87% of the total HCA amount) [23], whereas p- coumaric, caffeic and ferulic acids are encountered in blueberry fruits [22]. Indeed, caffeic acid is the most abundant in fruits (between 75 and 100% of the total HCA content) with the highest quantities in the range of 0.5 to 2 g in blueberries, kiwis, plums, cherries, and apples, whereas ferulic acid is Nutrients 2020, 12, 2190 3 of 30 acids are encountered in blueberry fruits [22]. Indeed, caffeic acid is the most abundant in fruits (between 75 and 100% of the total HCA content) with the highest quantities in the range of 0.5 to 2 g in blueberries, kiwis, plums, cherries, and apples, whereas ferulic acid is ubiquitous in cereal grains, which represent its major dietary source [24]. For example, ferulic acid is the prevalent phenolic acid in barley brans and seeds [22] and is also present in blueberries and blackberries ranging from 2.99 to 16.97 mg/g fresh weight [25]. Similarly, the levels of p-coumaric and caffeic acids in blueberry fruits varies from 0.40 to 15.78 and 1.38 to 6.32 mg/g fresh weight, respectively [25]. The most abundant HCAs in cranberry fruit are p-coumaric and sinapic acids with approximately 0.25 and 0.21 g/kg fresh weight, respectively [26]. All major HCAs are also present in numerous vegetables, with an average amount of total phenolic acids up to 32.0 mg/100 g fresh weight [27]. The major soluble HCAs identified in breeding vegetables are chlorogenic acids (eggplant, carrot, basil, spinach, Chinese cabbage, parsnip, lettuce, pepper, cauliflower, turnip, green bean, tomato), p-coumaric acid (radish, pepper, cauliflower, white cabbage, onion, zucchini, cucumber), ferulic acid (red beet, radish, pepper, turnip, cucumber), caffeic acid (carrot, broccoli, zuccini) and sinapic acid (broccoli, Chinese cabbage, cauliflower, turnip, white cabbage, pea) [27]. In another study, ferulic acid and caffeic acid were identified at high concentrations in spinach (18.0–41.4 mg/kg dry weight) and garlic (1.7–28.3 mg/kg dry weight), respectively, while chlorogenic acid was determined as the most abundant HCAs in artichoke (37.8–734.7 mg/kg dry weight) [28].