Critical Reviews in Food Science and Nutrition ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: https://www.tandfonline.com/loi/bfsn20 Pharmacological potential of methylxanthines: Retrospective analysis and future expectations João Monteiro, Marco G. Alves, Pedro F. Oliveira & Branca M. Silva To cite this article: João Monteiro, Marco G. Alves, Pedro F. Oliveira & Branca M. Silva (2019) Pharmacological potential of methylxanthines: Retrospective analysis and future expectations, Critical Reviews in Food Science and Nutrition, 59:16, 2597-2625, DOI: 10.1080/10408398.2018.1461607 To link to this article: https://doi.org/10.1080/10408398.2018.1461607 Accepted author version posted online: 06 Apr 2018. Published online: 15 May 2018. Submit your article to this journal Article views: 351 View related articles View Crossmark data Citing articles: 5 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=bfsn20 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 2019, VOL. 59, NO. 16, 2597–2625 https://doi.org/10.1080/10408398.2018.1461607 Pharmacological potential of methylxanthines: Retrospective analysis and future expectations Jo~ao Monteiroa, Marco G. Alves b, Pedro F. Oliveirab,c, and Branca M. Silvad aMass Spectrometry Centre, Department of Chemistry & CESAM, University of Aveiro, Campus Universitario de Santiago, Aveiro, Portugal; bDepartment of Microscopy, Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; cInstitute of Health Research an Innovation (i3S), University of Porto, Porto, Portugal; dUniversity of Beira Interior (UBI), Covilh~a, Portugal ABSTRACT KEYWORDS Methylated xanthines (methylxanthines) are available from a significant number of different botanical Caffeine; diabetes; species. They are ordinarily included in daily diet, in many extremely common beverages and foods. methylxanthine; Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The neurodegenerative diseases; supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that theobromine; theophylline have been attributed to these compounds through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacologic applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come. 1. Introduction have shown promise and were hinted as potential therapeutical tools. The current therapeutical uses in medicine are summa- There are compelling historical and anthropological evidences rized in Fig. 1, and will be discussed in later sections. The of methylxanthines being included in human diet for a very molecular mechanisms involved in the beneficial effects of long time. Nowadays, the consumption of products containing methylxanthines in various scopes will also be discussed. methylxanthines is undeniably widespread and very common in human populations. And other than the more traditional dietary sources of methylxanthines, like coffee, tea or chocolate, there are other methylxanthine-containing products that are 2. Methylxanthine chemistry and analysis gathering increased popularity, but also raising some concerns. Methylxanthines are heterocyclic organic compounds that are That is the case of energetic drinks and food supplements, methylated derivatives of xanthine, therefore comprising coupled which often contain significantly increased amounts of methyl- pyrimidinedione and imidazole rings (Talik, Krzek, and Ekiert xanthines with regard to the traditional sources. Caffeine is the 2012). Caffeine (1,3,7-trimethylxanthine), theophylline (1,3- more thoroughly studied methylxanthine so far, probably due dimethylxanthine) and theobromine (3,7-dimethylxanthine) are to the high prevalence of its consumption in present diet. Meth- the methylxanthines most frequently available from natural sour- ylxanthine therapeutic properties have been reported in a num- ces (Fig. 2). They differ in the number (caffeine has three, the ber of pathologic contexts. They have been used in medicine others two) and position of N-CH3 groups. Paraxanthine for decades in different medical scopes, namely respiratory (1,7-dimethylxanthine), another relevant methylxanthine, is not disease (Lam and Newhouse 1990), cardiovascular disease produced by plants but appears as a product of caffeine metabo- (Batterman et al. 1959) and cancer (Hayashi et al. 2005; Kimura lism, namely in humans (Nehlig 2015). Methylxanthines are pres- et al. 2009). However, the mechanisms underlying the benefi- ent in nearly 100 species of 13 orders of the Plant Kingdom cial action of methylxanthines in such conditions have not (Ashihara and Crozier 1999; Ashihara and Suzuki 2004), includ- always been clarified. ing tea (Camellia sinensis L.), coffee (Coffea sp.) and cacao (Theo- Herein, we discuss the historical relevance of methylxan- broma cacao L.). Caffeine is present in Coffea species (0.4 to 2.4% thine use in medicine and the emerging contexts where they dry weight (Mazzafera and Carvalho 1991)) and in the tea plants CONTACT Branca M. Silva [email protected] Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, Covilh~a, Portugal. Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/bfsn. © 2018 Taylor & Francis Group, LLC 2598 J. MONTEIRO ET AL. physiological action. These are adenosine receptors antagonism, phosphodiesterase inhibition, modulation of the action of recep- tors and regulation of intracellular calcium levels through ryano- dine channels (Chen and Chern 2011;Choietal.1988;Dentetal. 1994; Liu and Meissner 1997; McPherson et al. 1991; Tazzeo et al. 2012)(Table 1). Antagonism of adenosine receptors is thought to be the main mechanism of methylxanthine action, and their activ- ity is thought to be exerted preferably by modulation of A1 and A2A receptors, which are inhibited in the mM range (Fredholm et al. 1999). There are many available technical approaches to extract, identify and quantify these compounds in different kinds of sam- ples (food, beverages and even biological fluids) and many of those techniques also aim the simultaneous determination of the main methylxanthines (caffeine, theobromine and theophylline) (Fig. 3). They commonly involve some kind of pre-treatment protocols to eliminate unwanted matrix interferences, usually involving liquid-liquid (Begas et al. 2007; Bendriss, Markoglou, and Wainer 2000; El-Yazigi et al. 1999; Krul and Hageman 1998; Figure 1. Chronology of methylxanthine medical use. Newton et al. 1981b; Van Soeren et al. 1996) or solid-phase extraction (Emara 2004;Fenske2006; Georga, Samanidou, and Camellia sinensis, Camellia assamica and Camellia taliensis (2– Papadoyannis 2000;Setchelletal.1987; Srdjenovic et al. 2008). 3%) (Ashihara, Sano, and Crozier 2008). Theobromine may be Methylxanthine extraction is usually based in sequential aqueous present in some Camellia species, although Theobroma cacao is extraction, followed by organic extraction (with dimethyl chlo- normally reported as its major natural source (Ashihara, Sano, ride, chloroform, methanol or n-hexane (Belscak et al. 2009; and Crozier 2008). Theophylline is abundant in tea species, but is Caudle, Gu, and Bell 2001; Hulbert et al. 1998; Unachukwu et al. also present in trace amounts in cocoa and coffee beans (Barnes 2010;Xia,Ni,andKokot2013)). Liquid chromatography (LC), 2013). Paullinia sp., Cola sp.andCitrus sp. also contain methyl- namely reversed-phase high-performance liquid chromatogra- xanthines (Atawodi et al. 2007; Baumann, Schulthess, and H€anni phy (RP-HPLC) has been the choice normally used for methyl- 1995; Kretschmar and Baumann 1999; Weckerle, Stutz, and Bau- xanthine separation and determination. Low pressure mann 2003). Regarding human consumption through dietary chromatography was also recently proposed as an analytical products, caffeine and theophylline (typically at much lower alternative for methylxanthine separation and screening in sam- amounts) may be ingested in coffee, tea, cola beverages and choc- ples (Santos and Rangel 2012). Methylxanthine identification olate (Stavric 1988a), although tea contains less caffeine than cof- and quantification is commonly spectrophotometrically per- fee (Gilbert et al. 1976). Tea and chocolate should account for formed (by DAD or UV, at or about 273 nm (Adams, Vande- most theobromine intake through diet (Stavric 1988c). mark, and Schmidt