(051A) Metabolism Of Mulberroside A And Oxyresveratrol By Human
Intestinal Bacteria And Liver Subcelluar Preparations
Author(s):Mei Mei,Ru Yan,Huichang Bi,Yitao Wang
Affiliation(s):Institute of Chinese Medical Sciences, University of Macau
Address:Block 3,University of Macau, Av. Padre Tomás Pereira Taipa, Macau, China
Background: Cortex Mori,the root bark of Morus alba L.,has been used extensively in traditional Chinese medicine as an antitussive and diuretic agent. Mulberroside A (MulA) is one of the major constituents in the water extract of the herb (Piaoet al.,2006) and showedvarious therapy-related effects(Kanet al.,2006; Chung et al., 2003). In vivo pharmacokinetic studies revealed anextremely low oral bioavailability (<1%)of MulAin the rat and oxyresveratrolpresented asa principal drug-related component in the plasma (Qiuet al.,1996).However, the in vivo fate of MulA in human and the determinant factorsremain unclear. In this study,MulAmetabolism by human intestinal bacteria and metabolic stability of MulAand the resultant oxyresveratrol in human liver were reported.Reactions were quantitatively determined using HPLC-UV and structural identification was performed on anHPLC-MS/MS system.Results:When incubated anaerobically with human intestinal bacteria,MulAdecreased rapidly to generate two monoglucosides of oxyresveratrol and oxyresveratrol sequentially. MulA remained intact in human liver subcelluar fractions, whereas oxyresveratrol was extensively transformed into four monoglucuronidated metabolites(minor: G1,G2,G3; major: G4)in the microsomes. The average velocity of oxyresveratrol glucuronidation within 30 min was 4.00 nmole/min/mg protein.The kinetic study showed that the formation of the predominantmetaboliteG4followed substrate inhibition kinetics with the apparent Km value of 10.99 μM. Further investigation of glucuronidation activity of recombinant UGT isozymes revealed a predominant role of UGT1A1 and UGT1A9 inG4 formation. UGT1A7 and UGT1A8 also contributed but to a much less extent.Neither sulfationnor phase I reaction wasobserved for oxyresveratrol.Conclusions:MulA might undergo a rapid hydrolysis by bacteria existing in the gut lumen after oral intake by human. As the potential main absorbed form of MulA,oxyresveratrol might be further extensively glucuronidated by UGT1A1 and UGT1A9 when entering the liver.(Supported by the National Basic Research Program of China (973 program, Grant No.:2009CB522707), the Science and Technology Development Fund of Macau (Ref. No: 049/2005/A-R1)and the Research Committee of MacauUniversity (Project No.:RG065/08-09S/WYT/ICMS)).
Keywordsmulberroside A; oxyresveratrol; hydrolysis; glucuronidation
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