ABSTRACT
Two new fungal polyketides with unusual skeleton, collecapsins A and B (1-2), along with two known macrolactins A and B (3-4), were isolated from the rice cultures of an endophytic fungus Colletotrichum capsici obtained from the fresh Siegesbeckia pubescens Makino. Their structures were established by a combination of NMR, HRESIMS, and IR analysis. The absolute configurations of 1 and 2 were determined on the detailed analysis of the modified Mosher's derivatives' spectra and its key NOEs correlations. In this case, the absolute configurations of all chiral centres of 1 were determined for the first time, showed that 1 is a C-6/C-8 epimer of colletruncoic acid methyl ester. Compounds 1-2 demonstrated promising lipid lowing activity via the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with IC50 values of 8.72 and 15.28 µM. Compounds 3-4 exhibited antibacterial activity with MIC values ranging from 0.25-25.8 µM.
ABSTRACT
PURPOSE: To explore the impact of UDP-glucuronosyltransferase polymorphisms (UGT1A9-118(dT) 9/10 , UGT1A9 CI399T, UGT1A9 C-440T and UGT2B7 G211T) on the pharmacokinetics of mycophenolic acid (MPA) in healthy Chinese volunteers. METHODS: We recruited ten healthy volunteers with no polymorphisms (control group), 11 homozygotes of mutants UGT1A9 CI399T and UGT1A9-118(dT) 9/10 , ten heterozygotes of UGT1A9 C440T and seven carriers of UGT2B7 211T from a total of 518 healthy Chinese volunteers. All the volunteers were orally administered a single dose of 1.5 g mycophenolate mofetil (MMF) after an overnight fast. Plasma was then collected 72 h after MMF administration. MPA, MPA-7-O-glucuronide (MPAG) and its acylglucuronide (AcMPAG) were detected by ultra-pressure liquid chromatography with UV detection. RESULTS: Compared with the control group, the UGT1A9 CI399T and UGT1A9-118(dT) 9/10 mutant homozygotes had higher MPAG plasma concentrations. Subjects with UGT1A9-440TC had enhanced MPA exposure while carriers of UGT2B7 211T had higher concentrations of the toxic metabolite, AcMPAG. CONCLUSIONS: The current results indicate that UGT1A9 and UGT2B7 genotypes could significantly alter MPA pharmacokinetics in healthy Chinese volunteers after a single oral dose of MMF.
Subject(s)
Glucuronosyltransferase/genetics , Immunosuppressive Agents/pharmacokinetics , Mycophenolic Acid/analogs & derivatives , Polymorphism, Genetic , Administration, Oral , Asian People , Gene Frequency , Genotype , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Linkage Disequilibrium , Male , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/blood , Mycophenolic Acid/pharmacokinetics , UDP-Glucuronosyltransferase 1A9 , Young AdultABSTRACT
Uridinediphosphoglucuronate-glucuronosyltransferase (UGT) is the most important enzyme of the body in phase II metabolism. UGT is widely distributed in multiple tissues, including liver, kidney and intestine, which metabolizes a large number of exogenous toxic substances and endogenous substances. Studies found that UGT1 A genetic polymorphism is one of the important reasons for the variability of glucuronic acid metabolism between individuals. This paper reviews the current concept and new advances on UGT gene mutation.
