Abstract
Coffea arabica L. is the most well‐known and studied Coffea taxa, which is very popular in both scientific and social fields. This comprehensive work was created in order to describe its phytochemical composition and to present the metabolism of caffeine, which is the most important alkaloid from this plant. The analytical methods used for caffeine determination such as chromatographic, electrochemical, and spectroscopic techniques are also presented. In addition, this work emphasizes the medicinal importance of caffeine, which can present both important beneficial and secondary effects for human body.
Keywords
- caffeine
- coffee
- phytochemistry
- analytical methods
- Coffea arabica
- medicinal importance
1. Introduction
The genus
There are some legends about the discovery of coffee seeds and their utilization as beverage and food. The coffee seeds initially were consumed as snacks. The seeds were mixed with animal fat, and these were eaten by people during their long trips [5]. A kind of wine was also obtained from the fermented fruits of coffee [6]. One story tells that in the fifteenth century, there was a goat herder who noticed the stimulating effect of the coffee fruits when his goats ate these berries. He went to the nearest monastery to tell the monks his experience and they started to drink it during their long morning prayers [5].
The caffeine consumption has a long history dating back to antiquity. There are more than 60 plant species, which have been identified as containing caffeine. Plants like coffee, guarana, yoco, mate, and cassina were successfully used for the preparation of caffeine‐containing beverages. According to history, tea is the oldest caffeine‐containing beverage which had already been mentioned by the Chinese emperor Shen Nung in 2737 B.C., and it had been listed in a Chinese dictionary in about 350 AD [6].
The Arabic countries used to prohibit the consumption of coffee among men by referring to the Koran. In the sixteenth century, special places were established in Constantinople where Turkish dignitaries were served with coffee. As Turkish men spent a lot of time in these establishments, the mosques began to be abandoned, so imams opposed to the coffee consumption, which was forbidden by a law ordered by Muhammad. Due to this reason, Sultan Murad banned the coffee consumption, but later this law was modified when the use of tobacco started to become more popular [7].
Nowadays, approximately 7 million tons of coffee is used for the preparation of the famous coffee beverage according to Food and Agriculture Organization of the United Nations [8].
2. Coffea arabica L.: geographical distribution, cultivation, and processing
The coffee crops are spread in Central and South America, Africa, and Asia leading to a total of about 11 million hectares of plantations and an annual yield of about 6 million tons of green coffee [11].
Coffee products are processed in two methods: wet and dry processes. The dry procedure is popular in Brazil and the other one in Central America. During the dry method, the fruits are dried in open air for 2–3 weeks before the fermentation step [11, 13]. In addition, the wet method can be used only for ripe fruit as the fermentation positively affects the quality of seeds, external morphological aspects, and the taste [11, 13].
The roasting process, which is responsible for the characteristic aroma of the seeds, takes place only in customer country at 200–250°C [14]. This roasting process presents three phases such as an initial drying phase (during this endothermic step, the wet is eliminated and the color is turned yellowish), the roasting phase (based on several complex pyrolytic reactions resulting in many chemical compounds which will confer the coffee aroma and taste, the beans are transformed to dark brown during exothermic and endothermic phases), and the cooling phase (using air or water in order to end the last exothermic process [14].
3. Phytochemical features of Coffea arabica L.
The plant part of the coffee being officially used is the seed (
The characteristic aroma of coffee appears during the roasting process. The principal volatile compounds include derivatives of: sulfur (thiols, hydrogen sulfide, thiophenes, thiazoles), pyrazine (pyrazine itself, thiol and furfuryl derivatives, alkyl derivatives), pyridine, pyrrole, oxazole, furan, aldehydes, ketones, and phenols [14, 15]. Caffeine is present in all plant parts with the highest concentration in the immature seeds. This alkaloid with a bitter taste can be quantitatively reduced during the roasting and decaffeination processes [16].
Caffeine can present autotoxic and inhibiting effect on the mitosis and cell plate formation in rootlet. Studies demonstrated that the cell divisions in root tips started only after that it was pushed away from the caffeine‐rich endosperm by elongation of the hypocotyl and maintained through the cell elongation. Caffeine is introduced into the embryonic cotyledons mostly after the cell division is completed there [17]. Some authors suggested that the physiological significance of caffeine could be the prevention of predation by animals and these alkaloids function as allochemicals in the pericarp and seeds [18]. Josef et al. mentioned in their work about insecticidal effect of caffeine, which can also synergize the effects of pesticides [19].
Polyphenols are another representative group from the coffee seeds composition containing kaempferol, quercetin, ferulic, sinapic, nicotinic, quinolic, tannic, and pyrogallic acids which present important effects such as antioxidant, hepatoprotective, antibacterial, antiviral, anti‐inflammatory, and hypolipidemic ones [2, 20–27]. In addition, caffeic, chlorogenic, p‐coumaric, ferulic and sinapic acids, rutin, quercetin, kaempferol, and isoquercitrin were identified in fruits of
In one of our previous study, a high phenolic content was observed in the immature pericarp of
4. Metabolism of caffeine in Coffea arabica L.
4.1. Biosynthesis of caffeine
Caffeine biosynthesis takes place in the upper leaves and in the pericarp, and it is absent in the second and third leaves, cotyledons, lower stem, and root. After the biosynthesis, caffeine is accumulated in the mature leaves of coffee, but when the seed starts growing inside the fruit, it is translocated through the membranes being accumulated in the endosperm. The final quantity of caffeine is reached in 8 months after flowering [10, 35].
The caffeine biosynthesis in leaves is age‐dependent which means that it occurs usually at the very early stages of the leaf development reaching a maximum when the leaves are fully opened. The same age‐dependent biosynthesis was observed in the fruits of coffee and in the leaves, flowers, and fruits of tea plants. Naoko and Hiroshi studied the levels of purine alkaloids and the metabolism of adenine in the first and in the second leaves from the shoot apices of coffee plants. Even though theobromine and caffeine were found in these leaves, theophylline was not detected. Studies showed that adenine was converted to theobromine and caffeine in the first leaves and the degradation of adenine nucleotides was low in both types of leaves [18].
Caffeine is 1, 3, 7-trimethylxanthine having a xanthine skeleton derived from purine nucleotides. The purine compound initially involved in the biosynthesis pathway of caffeine is xanthosine, which is a substrate for the methyl group donated by
The caffeine synthesis is affected mostly by the enzymes activity, which can appear as limiting factors in the biosynthesis: xanthosine N‐methyltransferase, 7‐methylxanthosine nucleosidase, 7‐methylxanthine N‐methyltransferase, and theobromine N‐methyltransferase. The observation from the tea leaves indicated that their activity is also affected by seasons [18]. Caffeine accumulation seems to be regulated by the genes, which encode N‐methyltransferase and caffeine (7‐N) demethylase [36].
4.2. Catabolism of caffeine
The catabolism of caffeine is a slow process, which begins with the removal of the three methyl groups from the skeleton resulting in xanthine which is further decomposed to CO2 and NH3. These degradation reactions are catalyzed by various demethylases that have different levels of activity in the
Even though the degradation of caffeine is negligible in the leaves of
The catabolism of caffeine can also be achieved by various bacteria like
Some studies elaborated by Suzuki also showed that theophylline and xanthine were more quickly metabolized in the immature fruit; meanwhile, the caffeine degradation was performed in both mature and immature coffee fruits. The results showed that adenine was a more effective precursor than guanine and L‐methyl‐methionine for the biosynthesis of N7‐methylxanthine, theobromine, and caffeine. These results underlined that the caffeine biosynthesis occurred mostly in immature fruits through methylation of N‐methylxanthine and theobromine; meanwhile, its biodegradation occurred through theophylline, which is accumulated after that the seed is full size and the fruit is mature [39].
5. Analytical methods used for caffeine determination
Caffeine is a deeply studied alkaloid and, as it presents a significant importance for science and human body, many analytical methods have been developed over the years for its determination. The aim of these analytical methods was to identify and quantify this compound with different origin (from plants, beverages, and medicines). The most important and the most used techniques are the chromatographic methods coupled with spectrometry which allow a qualitative and quantitative determination of caffeine. Since these methods are quite expensive, there are a lot of scientific reports about different new low cost techniques. Electroanalytical methods recently became more popular since they are faster, more convenient, present lower costs, and are environmentally friendly in comparison with the other conventional analytical methods.
5.1. Chromatographic methods
The biochemical diversity of wild accessions of
Mazwfera et al. used HPLC method for qualitative and quantitative determinations of caffeine, theobromine, and theophylline in aqueous extracts of endosperm from immature and mature fruits of
Nowadays, science also pays attention for low‐pressure chromatography, which presents advantages such as easier assembly and handling, lower implementation cost, and more widespread application regarding separation of neutral or ionic compounds than other separation techniques. By using this method, caffeine was determined from six different coffee beverages: three regular, one decaffeinated, one soluble, and one chicory blended coffees. The results showed similar values for caffeine compared with the reference method (HPLC‐UV) with 5% relative deviations, with no signal for theobromine or theophylline. Even though low‐pressure chromatography uses a short column which implies reduced resolution, this methodology can be a competitive alternative to usual HPLC for caffeine determination in different materials due to its advantages such as higher determination rate, lower consumption of reagents, and no need to degas the mobile phase [42].
5.2. Spectroscopic methods
Frizzarin used the dispersive liquid‐liquid microextraction and spectrophotometric determination for caffeine in different coffee beverages. This lab‐in‐syringe sequential injection analysis system is a fast and simple procedure, which uses dichloromethane with high extraction capacity and good selectivity and methanol as dispersing agent. The developed technique presented linear response range from 2 to 75 mgL−1, limit of detection of 0.46 mgL−1 and limit of quantification of 1.54 mgL−1, being successfully applied for caffeine determination from brewed, instant, and decaffeinated coffee samples [43].
For the determination of caffeine, formic acid, trigonelline, and 5‐(hydroxyl‐methyl) furfural, there was applied the proton nuclear magnetic resonance technique (1H NMR) without any derivatization. The limits of detection were 1.32 mg/g for caffeine, 0.58 mg/g for trigonelline, and 0.30 mg/g for 5‐(hydroxyl‐methyl) furfural. In addition, HPLC was also used for the determination of these compounds employing a diode‐array detector at 273 nm for caffeine, 265 nm for trigonelline, and 284 nm for 5‐(hydroxyl‐methyl) furfural [44].
Alesso used spectrofluorimetric method for caffeine determination, which was developed by using the quenching effect on fluorescent emission of bovine serum albumin molecule (
A comparative study about caffeine content in roasted ground coffee and in China black tea was performed using a liquid‐liquid extraction. A simple and rapid spectrophotometric method was described for the determination of caffeine indicating that caffeine concentration in roasted coffee is lower than its concentration in black tea [46].
5.3. Electrochemical methods
Rotko and Beczkowska elaborated a Nafion covered lead film sensor leading to a sensitive, selective, and low cost method applied for caffeine determination in tea, coffee, soft and energy drink samples, and pharmaceutical products. Two anodic peaks were detected at 0.86 and 1.40 V (versus Ag/AgCl) in acidic medium, and the corresponding detection limits were equal to 1.7 × 10−8 and 2.2 × 10−7 molL−1, respectively, at 120 seconds of accumulation time. The results were in good agreement with the concentrations mentioned by the manufacturer and with those reported by using the spectrophotometric method [47].
Similar studies were reported by Gao et al. who modified a glassy carbon electrode (GCE) with large mesoporous carbon and Nafion composites (LMC/Nafion) achieving a simultaneous determination of theophylline and caffeine in serum and beverages. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were employed for the investigation of the electrochemical behaviors of theophylline and caffeine on the LMC/Nafion/GCE. Simultaneous determination of these two alkaloids was successfully obtained at the modified electrode since peak‐to‐peak separation of the two DPV peaks was about 150 mV. The sensor performances included detection limits of theophylline and caffeine of 0.37 and 0.47 µM, and a linear range between 0.8–180.0 and 1.3–230.0 µM, respectively [48].
The boron doped diamond electrode was also successfully used for simultaneous determination of caffeine and chlorogenic acid by CV and adsorptive stripping voltammetry, applied on commercial beverages. Various experimental parameters such as dependence of peak current and potential on pH, scan rate, and accumulation time were optimized. The oxidation peak potentials of caffeine and chlorogenic acid from binary mixtures were separated with 0.4 V in acidic medium by employing square‐wave stripping voltammetry. The analytical performances of this sensor indicated detection limits of 0.107 mgmL−1 (5.51·10−7 M) for caffeine and of 0.448 mgmL−1 (1.26 × 10−6 M) for chlorogenic acid [49].
Samanidou reviewed in her work several electroanalytical methods for caffeine determination. One example was constituted by polymer‐modified glassy carbon electrode, which was electropolymerized with 4‐amino‐3‐hydroxynaphthalene sulfonic acid. This sensor was suitable for a high sensitive, selective, and stable caffeine determination in coffee without any interference. The polymer‐modified electrode presented a linear range of 6 × 10−8–4 × 10−5 molL−1 and a detection limit of 1.37 × 10−7 molL−1 [44]. Other authors employed 1,4‐benzoquinone modified carbon paste electrode for indirect voltammetric determination of caffeine by using square wave voltammetry (SWV) and CV with detections limits of 0.3 and 5.1 μmolL−1, respectively [44].
Fritea et al. studied the formation of inclusion complexes between
6. Medicinal importance of coffee and caffeine
6.1. Ethnomedicinal knowledge of coffee
There are several references related to the application of coffee plants in traditional medicine underlying multiple healing potentials. In addition to the official drug (
Ross presented an ethnomedicinal map about the use of
In traditional medicine, the coffee coal was used for the inflammatory diseases of mouth and pharynx, but also it was used as a treatment of festering wounds [56]. In Nepal,
There are information about utilization of coffee leaves and seeds as infusion or decoction having different regional names such as “giser” in Yemen [2, 12]. Native people from Ethiopia drank a beverage named “hoja” for diarrhea and nausea, which were caused by poisoning [2, 59]. In some regions of Indonesia and Ethiopia, people used to prepare a tea from
Schmid et al. presented a study about the veterinary use of coffee in Swiss provinces indicating that farmers used coffee as a beverage to treat the reproductive, gastrointestinal, and metabolic disorders and infertility in animals. The authors showed that a subcutaneous injection of 10 mL coffee seed extract increased the healing rate of the newborn calves from diarrhea in 30% of the cases compared with the control subjects [2, 61].
6.2. Medicinal importance of coffee
The seed extracts of
Nowadays, many decaffeinated beverages are produced in order to overcome the negative withdrawal effects of caffeine by using different extraction methods, which involve some toxic solvents. Due to these methods, they may be harmful for the human body; therefore, many studies were performed in order to obtain new and less toxic extraction methods. Among these new techniques, it can be mentioned: the microbiological caffeine degradation by using
Ross mentioned in his work many scientific tests about the topical utilization of green seed extracts. The results showed that these extracts have a significant anti‐inflammatory activity. Other tests made on mice showed that the extracts of dried seeds have anticancer effect and they can also decrease blood sugar levels. However, seven cups of coffee per day with alcohol and cigarette can increase the suicidal tendency and the gastric acid level [2, 53]. The regular consumption of coffee mainly reduces the occurrence of kidney and liver cancers; meanwhile, premenopausal, breast, and colon cancers are less influenced. These effects are attributed to the content in caffeine, diterpenoids, caffeic acid, polyphenols, essential oils, and heterocyclic molecules [2, 66].
Cooper and Kronenberg tested the topical effect of coffee seed extract on 30 patients with dermatological problems. During this study, the product was applied on the whole facial area of 20 patients. In the case of 10 patients, it was applied only on the half of their face and the remaining area was treated with a placebo cream. The investigated cream presented noticeable effects such as appearance of fine lines and reduction of wrinkles and pigmentation [2, 67].
Jessen et al. have proved that thermogenic effect of nicotine can be improved by caffeine. They have studied this effect by using chewing gums with different concentration of nicotine and caffeine. They have found that the thermogenic effect of 1 mg of nicotine can be doubled by 100 mg of caffeine; therefore, caffeine could be used for weight gain prevention after smoking cessation [68]. It was also demonstrated that regular consumption of coffee presented benefits for the respiratory system in patients with asthma and smokers. In addition, the regular coffee consumption can reduce the occurrence probability of type II diabetes by 60%. The effect was not generated by caffeine since both caffeinated and decaffeinated beverages were studied obtaining the same result. Therefore, the compounds which are responsible for this effect are still unknown. Due to this reduced risk for diabetes development, coffee may be indicated as “functional food” efficient for the metabolic diseases prevention. Coffee presents high antioxidant properties due to the presence of flavonoids and polyphenols in its composition. The antioxidant activity was significantly increased after consumption of unfiltered coffee because of the glutathione increase [2, 69, 70].
Wagemaker et al. characterized the lipid fraction of the coffee seeds determining the variable concentration of wax, oil, and unsaponifiable material in the case of 10
Other studies reported that isoquercitrin and rutoside had anti-atherosclerotic effect, quercitrin had positive chronotropic, positive inotropic, and anti‐arrhythmic effects, which were tested on guinea pigs. Both quercetin and rutoside are used as therapeutic agents for capillary fragility and phlebosclerosis [2, 22]. Some flavonoids such as rutoside, gossypin, naringenin, (+)‐Cyanidanol‐3, quercetin, kaempferol, and rutin exhibit antiulcer activity by enhancing the gastric protection conferred by mucous content and inhibiting the platelet activating factor. Quercetin, kaempferol, and rutin showed antidiarrhetic effect and also benefits in other intestinal diseases since their actions are mediated through α2‐adrenergic and calcium systems. Some flavonoids such as rutin and venorutin were also proved to exhibit hepatoprotective effects. In addition, kaempferol, rutoside, and quercetin showed antioxidant, antiviral, antifungal, antibacterial, anti‐inflammatory, and antiallergic activity [22].
In one of our previous studies, the antioxidant activity of three
The hepatoprotective effect of coffee brews was proven by Lima et al. The two enzymes (aspartate aminotransferase and alanine aminotransferase)that are relevant for liver damage, the thiobarbituric acid reactive species, and total lipids, all were decreased. This effect was not negatively influenced by decaffeination process; meanwhile, it was indicated that the roasted coffee brews had a better protection against liver disease compared with green coffee brews [2, 72]. The vascular effects of coffee polyphenols were investigated by Ochiai et al., and the results showed that the peripheral endothelial function was improved after glucose loading in healthy person due to the ingestion of coffee polyphenols; meanwhile, no radical changes of the antioxidant activity were noticed [2, 73]. Chandra successfully assessed the
6.3. Medicinal importance of caffeine
Caffeine is absorbed 99% from stomach (20%) and small intestine (80%) [75]. The most popular effect of caffeine is its stimulant effect on the central nervous system. Moreover, there is a wide range of various effects that are also attributed to caffeine such as increase of the painkillers effect, reduction of tiredness and of migraine (as it has a vasoconstrictor activity in the brain), increase of the stomach acid secretion, stimulation of the heart function (with hypertensive effects), stimulation of kidney function (with diuretic effect), stimulation of respiration, and decrease of the vitamin B concentration [2]. In addition, it is supposed that the occurrence of Parkinson’s disease may be reduced by a regular consumption of coffee and cola [2].
Armanian showed that this alkaloid presents significant preventive effect of apnea in premature infants. Only 15.4% of the infants treated with caffeine have developed apnea in comparison with 61.5% of the control group [76].
As it was mentioned before, caffeine has a lot of beneficial effects, but in excess, it can generate plenty of secondary effects on the gastrointestinal, central nervous, circulating, and respiratory systems such as intestinal irritability, vomiting, diarrhea, stomach ulcers, tremors, sleep disturbances, headache, hallucinations, epileptic convulsions, high blood pressure, arrhythmic tachycardia, numbness, muscle spasms, and respiratory paralysis [2]. The excessive coffee consumption can lead to caffeinism which is an addiction because caffeine stimulates the central nervous system and also possesses negative withdrawal effects. Due to those secondary effects, coffee consumption should be avoided by people having cardio‐vascular, kidney, neurological and gastric diseases, hyperthyroidism, and caffeine sensitivity [2]. In addition, caffeine is not recommended during pregnancy and lactation as it can cause spontaneous abortion and it can be secreted in the breast milk [2].
7. Conclusions
Based on this comprehensive work, we can conclude that
References
- 1.
Davis AP, Chester M, Maurin O, Fay MF. Searching for the relatives of Coffea (Rubiaceae, Ixoroidae): The circumscription and phylogeny of Coffeae based on plastid sequence data and morphology. American Journal of Botany. 2007; 94 :313–329 - 2.
Patay ÉB, Bencsik T, Papp N. Phytochemical overview and medicinal importance of Coffea species from the past until now. Asian Pacific Journal of Tropical Medicine. 2016; 9 (12):1127–1135 - 3.
Tesfaye K, Govers K, Bekele E, Borsch T. ISSR fingerprinting of Coffea arabica throughout Ethiopia reveals high variability in wild populations and distinguishes them from landraces. Plant Systematics and Evolution. 2013;300 (5):881–897 - 4.
Rohwer JG. A Trópusok Növényei. Budapest: Magyar Könyvklub; 2002. p. 148 - 5.
Crozier A, Ashihara H, Tomás BF. Teas, cocoa and coffee. In: Plant Secondary Metabolites and Health. Chichester: Blackwell Publishing; 2012. pp. 4–5 - 6.
Barone JJ, Roberts HC. IV Human Consumption of Caffeine. Berlin: Springer; 1984. pp. 59–73 - 7.
Rácz J. Növénynevek Enciklopédiája. Az Elnevezések Eredete, A Növények Kultúrtörténete És Élettani Hatása. Budapest: Tinta Könyvkiadó; 2010. pp. 393–395 - 8.
Baeza G, Benavent MA, Sarriá B, Goya L, Mateos R, Bravo L. Green coffee hydroxycinnamic acids but not caffeine protect human HepG2 cells against oxidative stress. Food Research International. 2014; 62 :1038–1046 - 9.
Brücher H. Tropische Nutzpflanzen. Berlin: Springer; 1977. pp. 459–468 - 10.
Janzen SO. Chemistry of Coffee. Hamburg: Elsevier; 2013. pp. 1085–1113 - 11.
Măndiță D. Ce știm și ce nu știm despre cafea. București: Editura Tehnică. 2008; 37 :9–14 - 12.
Nowak B, Schulz B. A Trópusok Gyümölcsei. Budapest: Magyar Könyvklub; 2002. pp. 165–166 - 13.
Patay ÉB, Nemeth T, Nemeth TS, Papp N. Coffea taxonok biológiai, fitokémiai és gyógyászati értékelése. Botanikai Közlemények. 2014; 101 (1–2):263–280 - 14.
Buffo RA, Freire CC. Coffee flavour: An overview. Flavour and Fragrance Journal. 2004; 19 :99–104 - 15.
Farah A. Coffee constituents. In: Coffee: Emerging Health Effects and Disease Prevention. 1st ed. John Wiley & Sons; New Jersey 2012. pp. 21–58 - 16.
Fattorusso E, Scafati OT. Modern Alkaloids. Structure, Isolation, Synthesis and Biology. Weinheim: Wiley; 2008. p. 58 - 17.
Friedman J, Waller GR. Caffeine hazards and their prevention in germinating seeds of coffee ( Coffea arabica L). Journal of Chemical Ecology. 1983;9 (8):1099–1106 - 18.
Fujimon N, Ashira H. Biosinthesis of theobromine and caffeine in developing leaves of Coffea arabica . Pkytochnnrury. 1994;36( 6):1359–1361 - 19.
Kretschmar JA, Baumann TW. Caffeine in citrus flowers. Phytochemistry. 1999; 52 :19–23 - 20.
Huang MT, Smart RC, Wong CQ, Conney AH. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12‐ O ‐Tetradecanoylphorbol‐13‐acetate. Cancer Research.1988;48 :5941–5946 - 21.
Mussatto SI, Ballesteros LF, Martins S, Teixeira JA. Extraction of antioxidant phenolic compounds from spent coffee grounds. Separation and Purification Technology. 2011; 83 :173–179 - 22.
Narayana KR, Reddy MS, Chaluvadi MR, Krishna DR. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. The Indian Journal of Pharmacology. 2001; 33 :2–16 - 23.
Yeh CT, Yen GC. Effects of phenolic acids on human phenolsulfotransferases in relation to their antioxidant activity. The Journal of Agricultural and Food Chemistry.2003;51: 1474–1479 - 24.
Naidu MM, Sulochanamma G, Sampathu SR, Srinivas P. Studies on extraction and antioxidant potential of green coffee. Food Chemistry. 2008; 107 :377–384 - 25.
Dziki UG, Świeca M, Dziki D, Kowalska I, Pecio L, Durak A, Seczyk L. Lipoxygenase inhibitors and antioxidants fromgreen coffee – mechanism of action in the light of potential bioaccessibility. Food Research International. 2014; 61 :48–55 - 26.
Gîrd CE, Nencu I, Costea T, Duțu LE, Popescu ML, Ciupitu N. Quantitative analysis of phenolic compounds from Salvia officinalis L. Leaves. Farmacia. 2014;62 :649–657 - 27.
Quiroz MLS, Campos AA, Alfaro GV, Rios OG, Villeneuve P, Espinoza MCF. Isolation of green coffee chlorogenic acids using activated carbon. The Journal of Food Composition and Analysis. 2014; 33 :55–58 - 28.
Patay ÉB, Németh T, Németh TS, Filep R, Vlase L, Papp N. Histological and phytochemical studies of Coffea benghalensis B. Heyne Ex Schult, compared withCoffea arabica L. Farmacia. 2016;64 (1):125–130 - 29.
Patay ÉB, Sali N, Koszegi T, Csepregi R, Balázs VL, Németh TS, Németh T, Papp N. Antioxidant potential, tannin and polyphenol contents of seed and pericarp of three Coffea species. Asian Pacific Journal of Tropical Medicine. 2016; 9 (4):366–371 - 30.
Campa C, Mondolot L, Rakotondravao A, Bidel LPR, Gargadennec A, Couturon E, Fisca PL, Rakotomalala JJ, Allemand CJ, Davis AP. A survey of mangiferin and hydroxycinnamic acid ester accumulation in coffee (Coffea) leaves: Biological implications and uses. Annals of Botany – London. 2012; 110 :595–613 - 31.
Talamond P, Mondolot L, Gargadennec A, Kochko A, Hamon S, Fruchier A, Campa C. First report on mangiferin (C‐glucosyl‐xanthone) isolated from leaves of a wild coffee plant, Coffea pseudozanguebariae (Rubiaceae). Acta Botanica Gallica. 2008;155 :513–519 - 32.
Mondolot L, Fisca PL, Buatois B, Talansier E, Kocho AD, Campa C. Evolution in caffeoylquinic acid content and histolocalization during Coffea canephora leaf development. Annals of Botany. 2006;98 (1):33–40 - 33.
Farah A, Donangelo CM. Phenolic compounds in coffee. The Brazilian Journal of Plant Physiology. 2006; 18 (1):23–36 - 34.
Alves RC, Casal S, Alves MR, Oliveira MB. Discrimination between arabica and robusta coffee species on the basis of their tocopherol profiles. Food Chemistry. 2009; 114 :295–299 - 35.
Ashihara H, Crozier A. Caffeine: A well known but little mentioned compound in plant science. Trends in Plant Science. 2001; 6 (9):407–413. - 36.
Ashihara H, Crozier A. Biosynthesis and catabolism of caffeine in low‐caffeine‐containing species of coffea. Journal of Agriculturaland Food Chemistry. 1999; 47 :3425–3431 - 37.
Baumann TW, Laser ED, Wanner H. 7‐methylxanthosine – an intermediate in caffeine biosynthesis. Phytochemistry. 1978; 17 (12):2075–2076 - 38.
Aniszewski T. Enzymes specifically involved in alkaloid biosynthesis. In: Alkaloid Chemistry, Biological Significance, Applications, and Ecological Role. Amsterdam: Elsevier; 2007. p. 176 - 39.
Suzuki T, Waller GR. Biosynthesis and biodegradation of caffeine, theobromine, and theophylline in Coffea arabica L. Fruits. Journal of Agrlcultural and Food Chemistry. 1984;32 :845–848 - 40.
Ky CL, Louarn J, Dussert S, Guyot B, Hamon S, Noiro M. Caffeine, trigonelline, chlorogenic acids and sucrose diversity in wild Coffea arabica L. andC. canephora P. accessions. Food Chemistry. 2001;75 :223–230 - 41.
Mazwfera P, Crozier A, Magalhae AC. Caffeine metabolism in Coffea arabica and other species of coffee. Phytochemistry. 1991;30 (12):3913–3916 - 42.
Santos JR, Rangel AOSS. Determination of caffeine in coffee using low‐pressure chromatography. In: Coffee in Health and Disease Prevention. London: Elsevier; 2015. pp. 983–991 - 43.
Frizzarin RM, Maya F, Estela JM, Cerdà V. Fully‐automated in‐syringe dispersive liquid‐liquid microextraction for the determination of caffeine in coffee beverages. Food Chemistry. 2016; 212 :759–767 - 44.
Samanidou VF. Determination of polyphenols and major purine alkaloids in coffee: An overview. In: Coffee in Health and Disease Prevention. London: Elsevier; 2015. pp. 971–981 - 45.
Alesso M, Fernandez LP. Caffeine determination by flow injection analysis employing bovine serum albumin as a fluorophore. Microchem Journal. 2016; 127 :165–169 - 46.
Purcărea C, Chis A, Vicas S, Fodor A. Comparative studies about caffeine content in roasted ground coffee and in China black tea. Analele Universitatii din Oradea. 2008; 7 :966–971 - 47.
Rotko KT, Beczkowska I. Nafion covered lead film electrode for the voltammetric determination of caffeine in beverage samples and pharmaceutical formulations. Food Chemistry. 2015; 172 :24–29 - 48.
Gao Y, Wang H, Guo L. Simultaneous determination of theophylline and caffeine by large mesoporous carbon/nafion modified electrode. Journal of Electroanalytical Chemistry. 2013; 706 :7–12 - 49.
Yardım Y, Keskin E, Sentürk Z. Voltammetric determination of mixtures of caffeine and chlorogenic acid in beverage samples using a boron‐doped diamond electrode. Talanta. 2013; 116 :1010–1017 - 50.
Fritea L, Tertis M, Topală T, Săndulescu R. Electrochemical and spectral study of cyclodextrins interactions with some pharmaceutical substances. Farmacia. 2013; 61 (6):1054–1068 - 51.
Câmpean A, Tertis M, Săndulescu R. Electrochemical behavior of some purine derivatives on carbon based electrodes. Central European Journal of Chemistry. 2011; 9 (3):466–473 - 52.
Câmpean A, Tertis M, Săndulescu R. Voltammetric determination of some alkaloids and other compounds in pharmaceuticals and urine using an electrochemically activated glassy carbon electrode. Central European Journal of Chemistry. 2011; 9 (4):688–700 - 53.
Ross IA. Medicinal Plants of the World. 3rd ed. New Jersey: Humana Press Inc; 2005. pp. 155–184 - 54.
Lamorde M, Tabuti JRS, Obua C, Collins KB, Lanyero H, Pauline BK, Bbosa GS, Lubega A, Okeng JO, Ryan M, Waako PJ, Concepta M. Medicinal plants used by traditional medicine practitioners for the treatment of HIV/AIDS and related conditions in Uganda. Journal of Ethnopharmacology. 2010; 130 :43–53 - 55.
Neuwinger HD. African Traditional Medicine. Stuttgart: Medpharm Scientific Publishers; 2000. p. 130 - 56.
Gruenwald J, Brendler T, Jaenicke C. PDR for Herbal Medicines. Montvale: Medical Economics Company; 2000. pp. 202–204 - 57.
Ghimire K, Bastakoti RR. Ethnomedicinal knowledge and healthcare practices among the Tharus of Nawalparasi district in central Nepal. Forest Ecology Management. 2009; 257 :2066–2072 - 58.
Tabuti JRS, Lye KA, Dhillion SS. Traditional herbal drugs of Bulamogi, Uganda: Plants, use and administration. Journal of Ethnopharmacology. 2003; 88 :19–44 - 59.
Belayneh A, Bussa NF. Ethnomedicinal plants used to treat human aliments in the prehistoric place of Harla and Dengego valleys, eastern Ethiopia. Journal of Ethnobiology and Ethnomedicine. 2014; 10 :18 - 60.
Cramer PJS. A Review of Literature of Coffee Research in Indonesia. Costa Rica: Miscellaneous publication; 1957. p. 175 - 61.
Schmid K, Ivemeyer S, Vogl C, Klarer F, Meier B, Hamburger M, Walkenhorst M. Traditional use of herbal remedies in livestock by farmers in 3 swiss cantons (Aargau, Zurich, Schaffhausen). Forsch Komplement Medicine. 2012; 19 :125–136 - 62.
Boros B, Jakabová S, Dörnyei A, Horváth GY, Pluhár ZS, Killár F, Felinger A. Determination of polyphenolic compounds by liquid chromatography‐mass spectrometry in thymus species. Journal of Chromatography A. 2010; 1217 :7972–7980 - 63.
Rodrigues F, Pereira RC, Pimentel FB, Alves RC, Ferreira M, Sarmento B, Amaral MH, Oliveira MBPP. Are coffee silverskin extracts safe for topical use? An in vitro and in vivo approach. Industrail Crops and Products. 2015; 63 :167–174 - 64.
Gokulakrishnan S, Chandraraj K, Gummadi SN. Microbial and enzymatic methods for the removal of caffeine. Enzyme and Microbiology Technology. 2005; 37 :225–232 - 65.
McCusker RR, Fuehrlein B, Goldberger BA, Gold MS, Cone EI. Caffeine content of decaffeinated coffee. Journal of Analytical Toxicology. 2006; 30 :611–613 - 66.
Nkondjock A. Coffee consumption and the risk of cancer. An overview. Cancer Letters. 2009; 277 :121–125 - 67.
Cooper R, Kronenberg F. Botanical Medicine. New Rochelle: Mary Ann Liebert; 2009. p. 51 - 68.
Jessen AB, Toubro S, Astrup A. Effect of chewing gum containing nicotine and caffeine on energy expenditure and substrate utilization in men. American Journal of Clinical Nutrition. 2003; 77 :1442–1447 - 69.
Bisht S, Sisodia SS. Coffea arabica : A wonder gift to medical science. Journal of Natural Pharmaceuticals. 2010;1:58–66 - 70.
Belguidoum K, Guebailia HA, Boulmokh Y, Houache O. HPLC coupled to UV–vis detection for quantitative determination of phenolic compounds and caffeine in different brands of coffee in the Algerian market. Journal of the Taiwan Institute of Chemical Engineers. 2014; 45 :1314–1320 - 71.
Wagemaker TAL, Carvalho CRL, Maia NB, Baggio SR, Filho OG. Sun protection factor, content and composition of lipid fraction of green coffee beans. Industrial Crops and Products. 2011; 33 :469–473 - 72.
Lima AR, Pereira RGFA, Abrahão SA, Zangeronimo MG, Paula FBA, Duarte SMS. Effect of decaffeination of green and roasted coffees on the in vivo antioxidant activity and prevention of liver injury in rats. Brazilian Journal of Pharmacognosy. 2013; 23 (3):506–512 - 73.
Ochiai R, Sugiura Y, Shioya Y, Otsuka K, Katsuragi Y, Hashiguchi T. Coffee polyphenols improve peripheral endothelial function after glucose loading in healthy male adults. Nutrition Research. 2014; 34 :155–159 - 74.
Chandra S, Chatterjee P, Dey P, Bhattacharya S. Evaluation of in vitro anti‐inflammatory activity of coffee against the denaturation of protein. Asian Pacific Journal of Tropical Biomedicine. 2012; 2 (1):178–180 - 75.
Burdan F. Caffeine in Coffee. Coffee in Health and Disease Prevention. London: Elsevier; 2015. pp. 201–207 - 76.
Armanian AM, Iranpour R, Faghihian E, Salehimehr N. Caffeine administration to prevent apnea in very premature infants. Pediatrics and Neonatology. 2016; 57 (5):408–412