Isolation of a Human Intestinal Bacterium That Transforms Mangiferin to Norathyriol and Inducibility of the Enzyme That Cleaves a C-Glucosyl Bond

Abstract

C-Glucosides, which are widely distributed among plants, are more resistant towards acid, alkaline and enzyme hydrolysis than O-glucosides. Even prolonged exposure to acid does not cleave the glucosyl bond of C-glucosides, in which glucose is attached by a carbon-carbon bond to the aglycone, to give the aglycone. 1) However, intestinal bacteria from human feces can cleave C-glucosyl bonds in various C-glucosides such as mangiferin, abrusin 2Љ-O-b-D-apioside, aloeresin A, aloesin, barbaloin, bergenin, homoorientin, puerarin and safflor yellow B. 2-8)Mangiferin (2-b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone), was originally isolated from Mangifera indica L. (Anacardiaceae). It is distributed among at least sixteen plant families including Anacardiaceae, Iridaceae and Gentianaceae. Studies in vitro have shown that mangiferin has antiviral activity against herpes simplex virus 9) as well as antioxidant, 10) and anti-HIV activity. 11) Mangiferin orally administered to rats or mice exerts biological antitumor, 11) antidiabetic, 12) antioxidant, 13) hepatoprotective 14) and immunomodulative 15) activities. However, the pharmacokinetic studies in rats given oral mangiferin have failed to detect mangiferin in plasma, 16) suggesting poor absorption. On the other hand, appreciable amounts of euxanthone (1,7-dihydroxyxanthone) and its glucuronides are excreted into the urine of rabbits given oral mangiferin, 17) indicating a unique metabolic transformation that involves elimination of a Cglucosyl chain and two phenolic hydroxyl groups. The transformation of mangiferin to norathyriol by human fecal flora in vitro ( Fig. 1) 5) indicates an important role of mangiferinmetabolizing bacteria in the disposition of norathyriol and its subsequent metabolites in vivo, as well as in the pharmacological activities of mangiferin. Norathyriol also exerts antiinflammatory, 18,19) vasorelaxation 20) and antiplatelet 21) activities. Therefore, the biotransformation of mangiferin should be thoroughly investigated.Here, we isolated and characterized a bacterium that transforms mangiferin to norathyriol. Furthermore, the novel enzyme that cleaved C-glucosyl was selectively inducible with mangiferin and apparently differs from a-and b-glucosidases. The C-glucosyl bond of C-glucosides generally tolerates acid and enzymatic hydrolysis. Many C-glucosides are cleaved by human intestinal bacteria. We isolated the specific bacterium involved in the metabolism of mangiferin (2-b b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone), C-glucosyl xanthone, from a mixture of human fecal bacteria. The anaerobic Bacteroides species named MANG, transformed mangiferin to the aglycone, norathyriol, suggesting cleavage of a C-glucosyl bond. However, B. sp. MANG cleaved C-glucosyl in a dose-and time-dependent manner only when cultivated in the presence of mangiferin. Cleavage was abolished by inhibitors of RNA and protein syntheses, such as rifampicin and chloramphenicol, respectively, indicating that the enzyme that cleaves C-glucosyl is induced by mangiferin....

Metabolism and Pharmacokinetics of Mangiferin in Conventional Rats, Pseudo-Germ-Free Rats, and Streptozotocin-Induced Diabetic Rats

“…In addition, Sanugul et al (2005) and Braune and Blaut (2011) have isolated human intestinal bacteria, named Bacteroides sp. MANG and CG19-1, respectively, both of which could transform mangiferin into its aglycone norathyriol in vitro.…”

“…Considering the antidiabetic effects of mangiferin, it is important to investigate its pharmacokinetics and metabolism in diabetic animals. Previous in vitro studies (Sanugul et al, 2005;Braune and Blaut, 2011;Liu et al, 2011) indicated that mangiferin might be metabolized into norathyriol by the intestinal flora. Thus, it is conceivable that the role of intestinal flora in the metabolism of mangiferin is critical and its alterations may affect the metabolic and pharmacokinetic behavior of mangiferin in vivo.…”

Antitumor Activity and DNA-Binding Investigations of the Zn(II) and Cu(II) Complexes with Isoeuxanthone

“…[1][2][3] These naturally occurring compounds and their synthetic analogs have been reported to exhibit multiple important pharmacological properties, such as anti-oxidant, anti-inflammatory, anti-malarial and anti-cancer activity, etc. [4][5][6][7][8][9] As shown in Fig. 1a, xanthones having three linear fused aromatic rings may be viewed as flavone derivatives in which the phenyl group is fused with the two aromatic rings.…”

“…[4][5][6][7][8][9] As shown in Fig. 1a, xanthones having three linear fused aromatic rings may be viewed as flavone derivatives in which the phenyl group is fused with the two aromatic rings.…”

Two Proteins, Mn2+, and Low Molecular Cofactor Are Required for C-Glucosyl-Cleavage of Mangiferin

“…Quantitative Analysis of Mangiferin and Its Product, Norathyriol, by HPLC 22) The conditions used for reversed phase HPLC (Shimadzu Co., Japan) were as follows: recorder, C-R6A Chromatopac; pump, LC-6A; system controller, SCL-6B; monitor, SPD-6A; injector, SIL-9A; column, YMC-Pack ODS-AP AP-302 (YMC Co., Kyoto, Japan); flow rate, 1 ml/min; detection, 260 nm; solvent system, 10-40% acetonitrile linear gradient in 0.1% trifluoroacetic acid.…”