A Review on the Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Geniposide, a Natural Product
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molecules Review A Review on the Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Geniposide, a Natural Product Mingqiu Shan 1,* ID , Sheng Yu 1, Hui Yan 1, Sheng Guo 1, Wei Xiao 2, Zhenzhong Wang 2, Li Zhang 1, Anwei Ding 1, Qinan Wu 1 and Sam Fong Yau Li 3 1 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China; [email protected] (S.Y.); [email protected] (H.Y.); [email protected] (S.G.); [email protected] (L.Z.); [email protected] (A.D.); [email protected] (Q.W.) 2 National Key Laboratory of Pharmaceutical New Technology for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China; [email protected] (W.X.); [email protected] (Z.W.) 3 Department of Chemistry, National University of Singapore, Singapore 117543, Singapore; [email protected] * Correspondence: [email protected]; Tel.: +86-025-8581-1519; Fax: +86-025-8581-1524 Received: 25 August 2017; Accepted: 10 October 2017; Published: 10 October 2017 Abstract: Iridoid glycosides are natural products occurring widely in many herbal plants. Geniposide (C17H24O10) is a well-known one, present in nearly 40 species belonging to various families, especially the Rubiaceae. Along with this herbal component, dozens of its natural derivatives have also been isolated and characterized by researchers. Furthermore, a large body of pharmacological evidence has proved the various biological activities of geniposide, such as anti-inflammatory, anti-oxidative, anti-diabetic, neuroprotective, hepatoprotective, cholagogic effects and so on. However, there have been some research articles on its toxicity in recent years. Therefore, this review paper aims to provide the researchers with a comprehensive profile of geniposide on its phytochemistry, pharmacology, pharmacokinetics and toxicology in order to highlight some present issues and future perspectives as well as to help us develop and utilize this iridoid glycoside more efficiently and safely. Keywords: geniposide; iridoid glycoside; natural product; pharmacokinetics; pharmacology; phytochemistry; toxicology 1. Introduction Iridoid glycosides are phytochemicals which naturally occur in many plants belonging to the families Scrophulariaceae, Rubiaceae, Gentianaceae and Caprifoliaceae, including some Traditional Chinese Medicines (TCMs). Among them, geniposide (methyl (1S,4aS,7aS)-1-(β-D-gluco- pyranosyloxy)-7-(hydroxylmethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate; C17H24O10; GS; Figure1) is particularly well known. In view of its chemical structure, this component is also considered as a glycoside consisting of one molecule each of genipin and glucose. To date, this natural product has been isolated and identified in nearly 40 plants, most of which are traditional phytomedicines and/or come from the family Rubiaceae. As far as bioactivities are concerned, GS exerts many pharmacological functions, including anti-inflammatory [1], antidiabetic [2], anti-oxidative [3], neuroprotective [4], hepatoprotective and choleretic effects [5]. GS is recorded as a characteristic component for the quality control of Gardenia jasminoides Ellis (G. jasminoides) fruits in the 2000–2015 editions of the Chinese Pharmacopoeia [6–9]. According to the national standard, this phytomedicine with a GS content above 1.8% could be considered as having adequate quality. Molecules 2017, 22, 1689; doi:10.3390/molecules22101689 www.mdpi.com/journal/molecules Molecules 2017, 22, 1689 2 of 29 Molecules 2017, 22, 1689 2 of 27 Additionally,content above in the 1.8% 2015 could edition, be considered GS as also as listedhaving as adequate the quantitative quality. Additionally, component in for the quality 2015 edition, evaluation of aboutGS as twenty also listed Chinese as the Patent quantitative Medicine component preparations for quality containing evaluationG. of jasminoides about twentyfruits, Chinese such Patent as Bazheng Medicine preparations containing G. jasminoides fruits, such as Bazheng mixture, Longdan Xiegan mixture, Longdan Xiegan pills, Qingkailing soft capsules, Niuhuang Shangqing soft capsules and pills, Qingkailing soft capsules, Niuhuang Shangqing soft capsules and Zhizi Jinhua pills [10]. On the Zhizi Jinhua pills [10]. On the other hand, in recent years, there have been many new findings on other hand, in recent years, there have been many new findings on the hepatotoxicity and the hepatotoxicitynephrotoxicity of and the nephrotoxicity natural product of[11,12], the natural which productmay limit [ 11its, 12usage], which as a candidate may limit drug its usagewith as a candidategood performance drug with good in some performance diseases. in some diseases. FigureFigure 1. 1.Chemical Chemical structure structure of of geniposide. geniposide. Although a large number of studies on GS have been carried out and a considerable amount of relevantAlthough literature a large has number been reported, of studies a comprehens on GS haveive been review carried that outprovides and aa considerablecomplete profile amount on of relevantthe phytochemistry, literature has beenpharmacology, reported, pharmacokinetics a comprehensive and review toxicology that of provides the active acomponent complete is profile still on the phytochemistry,lacking. In the present pharmacology, study, with the pharmacokinetics help of some scientific and toxicologysearch engines of theand activedatabases, component including is still lacking.Google In theScholar, present Web study, of Science, with thePubmed help ofand some Chinese scientific National search Knowledge engines Infrastructure and databases, (CNKI), including Googlewe Scholar,summarize Web the of recent Science, research Pubmed progress and Chineseof the above National aspects. Knowledge In addition, Infrastructure some further studies (CNKI), we and future perspectives were also proposed. We hope that this review would prove helpful to summarize the recent research progress of the above aspects. In addition, some further studies and researchers to ensure that the GS will have an effective and safe application. future perspectives were also proposed. We hope that this review would prove helpful to researchers to ensure2. Sources that the GS will have an effective and safe application. 2. SourcesTo our knowledge, researchers isolated and identified GS from Gardenia jasminoides forma grandiflora (Lour.) Makino as an iridoid glycoside-type natural product in the 1960s [13]. Since then, thisTo ourcompound knowledge, has been researchers found in nearly isolated 40 plants and, identifiedthe majority GS of which from Gardeniabelong to the jasminoides Rubiaceaeforma grandiflora(Table 1). (Lour.) Some of Makino the plants asan are iridoid famous glycoside-type phytomedicines naturalthat have product been used in the in 1960sthe clinic [13 ].for Since then,thousands this compound of years has in beenChina found and Southeast in nearly Asia, 40 plants, such as the G. majorityjasminoides of (Zhizi), which belongRehmannia to theglutinosa Rubiaceae (TableLibosch.1). Some (Dihuang), of the plants Eucommia are famous ulmoides phytomedicines Oliv. (Duzhong) that and have Achyranthes been used bidentata in the clinicBlume for (Niuxi). thousands of yearsAmong in Chinathem, andG. jasminoides Southeast is Asia,a fundamental such as G. plant jasminoides source of(Zhizi), GS withRehmannia a considerable glutinosa contentLibosch. (Dihuang),(3.3–8.56%)Eucommia found ulmoidesin the fruitsOliv. of (Duzhong)dry weight (DW) and Achyranthes [14]. This iridoid bidentata glycosideBlume has (Niuxi). been found Among and them, isolated from various parts of this phytomedicine, including leaves, flowers, fruits and tubers. G. jasminoides is a fundamental plant source of GS with a considerable content (3.3–8.56%) found in Furthermore, there were also several varieties of the species G. jasminoides containing GS, including the fruitsGardenia of dryjasminoides weight cv. (DW) fortuneana [14]. This Hara, iridoid Gardenia glycoside jasminoides has forma been grandiflora found and (Lour.) isolated Makino from and various partsGardenia of this jasminoides phytomedicine, var. radicans including (Thunb.) leaves, Makino. flowers, There fruitswere also and some tubers. studies Furthermore, on the GS contents there were alsoin several other varietiesherbal medicines of the speciesfrom differentG. jasminoides productioncontaining areas, which GS, report including variousGardenia amounts jasminoides such as cv. fortuneana0.2035–0.4381% Hara, Gardenia (DW) for jasminoides Rehmanniaforma glutinosa grandiflora Libosch. (Lour.)roots [15], Makino 0.0699–0.1135% and Gardenia (DW) jasminoides for var. Scrophulariaradicans (Thunb.) ningpoensis Makino. Hemsl. Thereroots [16], were and also 0.0173–0.5811% some studies (DW) on the for GSEucommia contents ulmoides in other Oliv. herbal medicinesbarks [17]. from different production areas, which report various amounts such as 0.2035–0.4381% (DW) for Rehmannia glutinosa Libosch. roots [15], 0.0699–0.1135% (DW) for Scrophularia ningpoensis Hemsl. roots [16], and 0.0173–0.5811% (DW) for Eucommia ulmoides Oliv. barks [17]. Molecules 2017, 22, 1689 3 of 29 Table 1. Plants containing geniposide. No. Plant Family Part References 1 Achyranthes bidentata Blume Amarathaceae roots [18] 2 Adina polycephala Benth. Rubiaceae branches and stems [19] 3 Alibertia sessilis (Vell.) K. Schum. Rubiaceae stems [20] 4 Biebersteinia heterostemon Maxim. Geraniaceae whole plants [21] 5 Castilleja tenuiflora