foods Review Effects of Phlorotannins on Organisms: Focus on the Safety, Toxicity, and Availability of Phlorotannins Bertoka Fajar Surya Perwira Negara 1,2, Jae Hak Sohn 1,3, Jin-Soo Kim 4,* and Jae-Suk Choi 1,3,* 1 Seafood Research Center, IACF, Silla University, 606, Advanced Seafood Processing Complex, Wonyang-ro, Amnam-dong, Seo-gu, Busan 49277, Korea; [email protected] (B.F.S.P.N.); [email protected] (J.H.S.) 2 Department of Marine Science, University of Bengkulu, Jl. W.R Soepratman, Bengkulu 38371, Indonesia 3 Department of Food Biotechnology, College of Medical and Life Sciences, Silla University, 140, Baegyang-daero 700beon-gil, Sasang-gu, Busan 46958, Korea 4 Department of Seafood and Aquaculture Science, Gyeongsang National University, 38 Cheondaegukchi-gil, Tongyeong-si, Gyeongsangnam-do 53064, Korea * Correspondence: [email protected] (J.-S.K.); [email protected] (J.-S.C.); Tel.: +82-557-729-146 (J.-S.K.); +82-512-487-789 (J.-S.C.) Abstract: Phlorotannins are polyphenolic compounds produced via polymerization of phloroglucinol, and these compounds have varying molecular weights (up to 650 kDa). Brown seaweeds are rich in phlorotannins compounds possessing various biological activities, including algicidal, antioxidant, anti-inflammatory, antidiabetic, and anticancer activities. Many review papers on the chemical characterization and quantification of phlorotannins and their functionality have been published to date. However, although studies on the safety and toxicity of these phlorotannins have been conducted, there have been no articles reviewing this topic. In this review, the safety and toxicity of phlorotannins in different organisms are discussed. Online databases (Science Direct, PubMed, MEDLINE, and Web of Science) were searched, yielding 106 results. Following removal of duplicates Citation: Negara, B.F.S.P.; Sohn, J.H.; and application of the exclusion criteria, 34 articles were reviewed. Phlorotannins from brown Kim, J.-S.; Choi, J.-S. Effects of seaweeds showed low toxicity in cell lines, invertebrates, microalgae, seaweeds, plants, animals (fish, Phlorotannins on Organisms: Focus mice, rats, and dogs), and humans. However, the safety and toxicity of phlorotannins in aquaculture on the Safety, Toxicity, and fish, livestock, and companion animals are limited. Further studies in these organisms are necessary Availability of Phlorotannins. Foods 2021, 10, 452. https://doi.org/ to carry out a systematic analysis of the safety and toxicity of phlorotannins and to further identify 10.3390/foods10020452 the potential of phlorotannins as functional foods, feeds, and pharmaceuticals. Academic Editors: Montaña Cámara Keywords: phlorotannins; toxicity; plant; invertebrates; animal; human and Patricia Morales Received: 19 January 2021 Accepted: 15 February 2021 Published: 19 February 2021 1. Introduction Phlorotannins are polyphenols found in brown seaweeds, consisting of phlorogluci- Publisher’s Note: MDPI stays neutral nol (Figure1) (1,3,5-trihydroxybenzene) units that are bonded to each other by different with regard to jurisdictional claims in pathways. They are found in the range of 126–650 kDa, and their concentration in dried published maps and institutional affil- brown seaweeds varies from 0.5% to 2.5% [1,2]. The concentration of phlorotannins in dried iations. brown seaweeds can differ according to the biological factors, such as age, size, and type of tissue, as well as environmental conditions, such as light intensity, water temperature, season, nutrient levels, and herbivory intensity. Phlorotannins are classified into four groups based on linkage, such as those with an Copyright: © 2021 by the authors. ether linkage (fuhalols and phlorethols), phenyl linkage (fucols), ether and phenyl linkages Licensee MDPI, Basel, Switzerland. (fucophloroethols), and dibenzodioxin linkage (eckols). Numerous phlorotannins have This article is an open access article been discovered from brown seaweeds, including eckol [3–5], phlorofucofuroeckol A [6–9], distributed under the terms and dieckol [2,7–20], 6,60-bieckol [21,22], 8,80-bieckol [23], 7-phloroeckol [24], fucodiphloroethol conditions of the Creative Commons G, phloroglucinol [14], and bifuhalol [25]. Among seaweeds, brown seaweeds including Attribution (CC BY) license (https:// Ecklonia cava, have been reported to produce higher concentrations of phlorotannins than creativecommons.org/licenses/by/ other marine phenolic compounds [12]. In brown seaweeds, phlorotannins act as UV 4.0/). Foods 2021, 10, 452. https://doi.org/10.3390/foods10020452 https://www.mdpi.com/journal/foods Foods 2021, 10, 452 2 of 19 Foods 2021, 10, x FOR PEER REVIEW 2 of 18 protectors and antioxidants, prevent stress and herbivory, and play an important role in the structure of the cell wall [14–16]. FigureFigure 1. The 1. basic The structurebasic structure of phlorotannins of phlorotannins are composed are composed of phloroglucinol of phloroglucinol units. units. PhlorotanninsEisenia bicyclis, are E. classified arborea, E. into cava, four E. kurome,groups E.based stolonifera, on linkage, Pelvetia such siliquosa, as thoseand withIshige an etherokamurae, linkageas (fuhalols well as from and thephlorethols), genera Cystophora phenyl linkageand Fucus (fucols),, contain ether phlorotannins and phenyl link- that agespossess (fucophloroethols), antidiabetic, antioxidant, and dibenzodioxin antitumor, linkage anti-inflammatory, (eckols). Numerous and anticancer phlorotannins proper- haveties [been26–28 discovered]. Furthermore, from brownE. cava seaweeds,contains eckol,including triphlorethol eckol [3–5], A, phlorofucofuroeckol fucodiphlorethol G, Adieckol, [6–9], dieckol dioxinodehydroeckol, [2,7–20], 6,6′-bieckol phloroglucinol, [21,22], 8,8′-bieckol and phlorofucofuroeckol [23], 7-phloroeckol A [24], [23 ],fucodi- and it phloroetholexerts antihypertensive G, phloroglucinol [29] and [14], skin-whitening and bifuhalol [25]. [12] effects.AmongE. seaweeds, kurome and brownE. bicyclis seaweedswere includingalso reported Ecklonia to containcava, have dieckol, been phlorofucofuroeckolreported to produce higher A, and concentrations eckol [30]. An of extract phloro- of tanninsE. arborea than, which other contains marine phenolic phlorofucofuroeckol-B, compounds [12]. eckol, In brown and phlorofucofuroeckol seaweeds, phlorotannins A [31], I. okamurae acthas as also UV protectors shown antiallergic and antioxidants, effect. Moreover, prevent stress the and brown herbivory, seaweed and play an importantcontains phloroglucinol and 6,60-bieckol and diphlorethohydroxycarmalol (DPHC) [32]. role in the structure of the cell wall [14–16]. Various biological activities have been reported for phlorotannins, including anti- Eisenia bicyclis, E. arborea, E. cava, E. kurome, E. stolonifera, Pelvetia siliquosa, and Ishige cancer [23], antioxidant [32], anti-inflammatory [33], antidiabetic, and neuroprotective [18] okamurae, as well as from the genera Cystophora and Fucus, contain phlorotannins that pos- activities. The biological activities exhibited by these compounds suggest that they are po- sess antidiabetic, antioxidant, antitumor, anti-inflammatory, and anticancer properties tentially useful as new ingredients in the food [34,35], feed, and pharmaceutical industries. [26–28]. Furthermore, E. cava contains eckol, triphlorethol A, fucodiphlorethol G, dieckol, Nonetheless, it is important to study the safety and toxicity of these compounds before dioxinodehydroeckol, phloroglucinol, and phlorofucofuroeckol A [23], and it exerts anti- the development of new products. In this regard, a review of the safety and toxicity of hypertensive [29] and skin-whitening [12] effects. E. kurome and E. bicyclis were also re- phlorotannins is urgently needed in view of their functionality and potential for industrial ported to contain dieckol, phlorofucofuroeckol A, and eckol [30]. An extract of E. arborea, applications. Many articles reviewing the characterization and quantitative analysis of which contains phlorofucofuroeckol-B, eckol, and phlorofucofuroeckol A [31], has also phlorotannin compounds [36–38], as well as the functionality of phlorotannins [2,27,39–42] shownhavebeen antiallergic published effect. to date.Moreover, However, the brown although seaweed studies I. okamurae on the safety contains and phloroglu- toxicity of cinolphlorotannins and 6,6′-bieckol have beenand diphlorethohydroxycarmalol conducted, there are no review (DPHC) papers [32]. on this topic. Therefore, thisVarious article reviews biological studies activities conducted have been to test reported the safety for andphlorotannins, toxicity of phlorotannins including anti- in cancervarious [23], organisms. antioxidant [32], anti-inflammatory [33], antidiabetic, and neuroprotective [18] activities. The biological activities exhibited by these compounds suggest that they are2. Materialspotentially and useful Methods as new ingredients in the food [34,35], feed, and pharmaceutical industries.Literature Nonetheless, search was it is conducted important systematically to study the safety based and onthe toxicity Systematic of these Reviews com- poundsand Meta-Analyses before the development (PRISMA) guidelines of new products. [43]. Online In this databases, regard, a review including of the Science safety Direct, and toxicityPubMed, of MEDLINE,phlorotannins and is Web urgently of Science needed databases in view were of their used. functionality The search strategy and potential focused foron industrial the terms applications. “phlorotannins” Many and