Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

In vitro glucuronidation of ochratoxin a by rat liver microsomes.

ABSTRACT: Ochratoxin A (OTA), one of the most toxic mycotoxins, can contaminate a wide range of food and feedstuff. To date, the data on its conjugates via glucuronidation request clarification and consolidation. In the present study, the combined approaches of ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), UHPLC-Orbitrap-high resolution mass spectrometry (HRMS) and liquid chromatography-multiple stage mass spectrometry (LC-MS(n)) were utilized to investigate the metabolic profile of OTA in rat liver microsomes. Three conjugated products of OTA corresponding to amino-, phenol- and acyl-glucuronides were identified, and the related structures were confirmed by hydrolysis with ?-glucuronidase. Moreover, OTA methyl ester, OT? and OT?-glucuronide were also found in the reaction solution. Based on these results, an in vitro metabolic pathway of OTA has been proposed for the first time.

SUBMITTER: Han Z

PROVIDER: S-EPMC3873705 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

In vitro glucuronidation of ochratoxin a by rat liver microsomes.

Han Zheng Z Tangni Emmanuel K EK Di Mavungu José Diana JD Vanhaecke Lynn L De Saeger Sarah S Wu Aibo A Callebaut Alfons A

Toxins 20131218 12

Ochratoxin A (OTA), one of the most toxic mycotoxins, can contaminate a wide range of food and feedstuff. To date, the data on its conjugates via glucuronidation request clarification and consolidation. In the present study, the combined approaches of ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), UHPLC-Orbitrap-high resolution mass spectrometry (HRMS) and liquid chromatography-multiple stage mass spectrometry (LC-MS(n)) were utilized to investigate the meta ...[more]

PMID: 24351721

Similar Datasets

In Vitro Glucuronidation of Wushanicaritin by Liver Microsomes, Intestine Microsomes and Expressed Human UDP-Glucuronosyltransferase Enzymes.

Project description:Wushanicaritin, a natural polyphenol compound, exerts many biological activities. This study aimed to characterize wushanicaritin glucuronidation by pooled human liver microsomes (HLM), human intestine microsomes and individual uridine diphosphate-glucuronosyltransferase (UGT) enzyme. Glucuronidation rates were determined by incubating wushanicaritin with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Reaction phenotyping, the relative activity factor (RAF) and activity correlation analysis were performed to identify the main UGT isoforms. Wushanicaritin glucuronidation in HLM was efficient with a high CLint (intrinsic clearance) value of 1.25 and 0.69 mL/min/mg for G1 and G2, respectively. UGT1A1 and 1A7 showed the highest activities with the intrinsic clearance (CLint) values of 1.16 and 0.38 mL/min/mg for G1 and G2, respectively. In addition, G1 was significantly correlated with β-estradiol glucuronidation (r = 0.847; p = 0.0005), while G2 was also correlated with chenodeoxycholic acid glucuronidation (r = 0.638, p = 0.026) in a bank of individual HLMs (n = 12). Based on the RAF approach, UGT1A1 contributed 51.2% for G1, and UGT1A3 contributed 26.0% for G2 in HLM. Moreover, glucuronidation of wushanicaritin by liver microsomes showed marked species difference. Taken together, UGT1A1, 1A3, 1A7, 1A8, 1A9 and 2B7 were identified as the main UGT contributors responsible for wushanicaritin glucuronidation.

| S-EPMC5618632 | biostudies-literature

In vitro glucuronidation of methyl gallate and pentagalloyl glucopyranose by liver microsomes.

Project description:Methyl gallate (MG) and pentagalloyl glucopyranose (PGG) are bioactive phenolic compounds that possess various pharmacological activities. However, the knowledge of hepatic metabolism of MG and PGG is limited. The purpose of this study was to investigate the in vitro glucuronidation of MG and PGG using liver microsomes from human (HLMs) and rats (Sprague-Dawley, SDRLMs; Wistar, WRLMs; and Gunn, GRLMs), and recombinant human uridine 5'-diphospho-glucuronosyltransferases (UGT) 1A1 and 1A9. The results demonstrated that liver microsomes catalyzed two mono-glucuronided MG (M1 and M2) formations but that UGT1A1 and 1A9 catalyzed only M1 formation. For PGG, a mono-glucuronided metabolite was mediated by liver microsomes or UGT1A9. However, a PGG glucuronide was absent in the UGT1A1 system. Additionally, all metabolites showed susceptibility to β-glucuronidases. Furthermore, the glucuronidation activities of PGG were lower than those of MG. The kinetic parameters of MG glucuronidation demonstrated that the SDRLMs and GRLMs were more similar to the HLMs than the WRLMs for the formations of M1 and M2, respectively and that the SDRLMs and HLMs preferentially contributed to M1, whereas the WRLMs and GRLMs showed the favored formation of M2. In conclusion, MG and PGG were subjectively glucuronided by liver microsomes to demonstrate species- and strain-dependent metabolism.

| S-EPMC7671852 | biostudies-literature

Inhibition of genistein glucuronidation by bisphenol A in human and rat liver microsomes.

Project description:Genistein is a natural phytoestrogen of the soybean, and bisphenol A (BPA) is a synthetic chemical used in the production of polycarbonate plastics. Both genistein and BPA disrupt the endocrine system in vivo and in vitro. Growing concerns of altered xenobiotic metabolism due to concomitant exposures from soy milk in BPA-laden baby bottles has warranted the investigation of the glucuronidation rate of genistein in the absence and presence (25 μM) of BPA by human liver microsomes (HLM) and rat liver microsomes (RLM). HLM yield V(max) values of 0.93 ± 0.10 nmol · min(-1) · mg(-1) and 0.62 ± 0.05 nmol · min(-1) · mg(-1) in the absence and presence of BPA, respectively. K(m) values for genistein glucuronidation by HLM in the absence and presence of BPA are 15.1 ± 7.9 μM and 21.5 ± 7.7 μM, respectively, resulting in a K(i) value of 58.7 μM for BPA. Significantly reduced V(max) and unchanged K(m) in the presence of BPA in HLM are suggestive of noncompetitive inhibition. In RLM, the presence of BPA resulted in a K(i) of 35.7 μM, an insignificant change in V(max) (2.91 ± 0.26 nmol · min(-1) · mg(-1) and 3.05 ± 0.41 nmol · min(-1) · mg(-1) in the absence and presence of BPA, respectively), and an increase in apparent K(m) (49.4 ± 14 μM with no BPA and 84.0 ± 28 μM with BPA), indicative of competitive inhibition. These findings are significant because they suggest that BPA is capable of inhibiting the glucuronidation of genistein in vitro, and that the type of inhibition is different between HLM and RLM.

| S-EPMC3286267 | biostudies-literature

Glucuronidation of drugs in humanized UDP-glucuronosyltransferase 1 mice: Similarity with glucuronidation in human liver microsomes.

Project description:Uridine 5'-diphosphate-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various endogenous and exogenous substrates. Among 19 functional human UGTs, UGT1A family enzymes largely contribute to the metabolism of clinically used drugs. While the UGT1A locus is conserved in mammals such as humans, mice, and rats, species differences in drug glucuronidation have been reported. Recently, humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) have been developed. To evaluate the usefulness of hUGT1 mice to predict human glucuronidation of drugs, UGT activities, and inhibitory effects on UGTs were examined in liver microsomes of hUGT1 mice as well as in those of wild-type mice and humans. Furosemide acyl-glucuronidation was sigmoidal and best fitted to the Hill equation in hUGT1 mice and human liver microsomes, while it was fitted to the substrate inhibition equation in mouse liver microsomes. Kinetic parameters of furosemide glucuronidation were very similar between hUGT1 mice and human liver microsomes. The kinetics of S-naproxen acyl-glucuronidation and inhibitory effects of compounds on furosemide glucuronidation in hUGT1 liver microsomes were also slightly, but similar to those in human liver microsomes, rather than in wild-type mice. While wild-type mice lack imipramine and trifluoperazine N-glucuronidation potential, hUGT1 mice showed comparable N-glucuronidation activity to that of humans. Our data indicate that hUGT1 mice are promising tools to predict not only in vivo human drug glucuronidation but also potential drug-drug interactions.

| S-EPMC4184567 | biostudies-literature

Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin.

Project description:Previous studies have shown the importance of the addition of albumin for characterization of hepatic glucuronidation in vitro; however, no reports exist on the effects of albumin on renal or intestinal microsomal glucuronidation assays. This study characterized glucuronidation clearance (CL(int, UGT)) in human kidney, liver, and intestinal microsomes in the presence and absence of bovine serum albumin (BSA) for seven drugs with differential UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B7 specificity, namely, diclofenac, ezetimibe, gemfibrozil, mycophenolic acid, naloxone, propofol, and telmisartan. The impact of renal CL(int, UGT) on accuracy of in vitro-in vivo extrapolation (IVIVE) of glucuronidation clearance was investigated. Inclusion of 1% BSA for acidic drugs and 2% for bases/neutral drugs in incubations was found to be suitable for characterization of CL(int, UGT) in different tissues. Although BSA increased CL(int, UGT) in all tissues, the extent was tissue- and drug-dependent. Scaled CL(int, UGT) in the presence of BSA ranged from 2.22 to 207, 0.439 to 24.4, and 0.292 to 23.8 ml · min(-1) · g tissue(-1) in liver, kidney, and intestinal microsomes. Renal CL(int, UGT) (per gram of tissue) was up to 2-fold higher in comparison with that for liver for UGT1A9 substrates; in contrast, CL(int, UGT) for UGT2B7 substrates represented approximately one-third of hepatic estimates. Scaled renal CL(int, UGT) (in the presence of BSA) was up to 30-fold higher than intestinal glucuronidation for the drugs investigated. Use of in vitro data obtained in the presence of BSA and inclusion of renal clearance improved the IVIVE of glucuronidation clearance, with 50% of drugs predicted within 2-fold of observed values. Characterization and consideration of kidney CL(int, UGT) is particularly important for UGT1A9 substrates.

| S-EPMC3310423 | biostudies-literature

Chlordane and heptachlor are metabolized enantioselectively by rat liver microsomes.

Project description:Chlordane, heptachlor, and their metabolites are chiral persistent organic pollutants that undergo enantiomeric enrichment in the environment. This study investigated the enantioselective metabolism of both chlordane isomers and heptachlor, major components of technical chlordane, by liver microsomes prepared from male rats treated with corn oil (CO) or inducers of CYP2B (PB; phenobarbital) and CYP3A enzymes (DX; dexamethasone), isoforms induced by chlordane treatment. The extent of the metabolism of all three parent compounds was dependent on the microsomal preparation used and followed the rank order PB > DX > CO. The mass balances ranged from 49 to 130% of the parent compound added to the microsomal incubations. Both cis- and trans-chlordane were enantioselectively metabolized to oxychlordane (EF = 0.45-0.89) and 1,2-dichlorochlordene (EF = 0.42-0.90). Heptachlor was metabolized enantioselectively, with heptachlor epoxide B (EF = 0.44-0.54) being the only metabolite. Interestingly, the direction on the enrichment for oxychlordane, 1,2-dichlorochlordene, and heptachlor epoxide differed depending on the microsomal preparation. These findings demonstrate that the direction and extent of the enantioselective metabolism of both chlordane isomers and heptachlor is P450 isoform-dependent and can be modulated by the induction of P450 enzymes.

| S-EPMC3748599 | biostudies-literature

The metabolism of gelsevirine in human, pig, goat and rat liver microsomes.

Project description:Gelsemium is a small genus of flowering plants from the family Loganiaceae comprising five species, three of which, Gelsemium sempervirens (L.) J. St.-Hil., G. elegans Benth and G. rankinii Small, are particularly popular. Compared with other alkaloids from G. elegans, gelsemine, gelsevirine and koumine exhibit equally potent anxiolytic effects and low toxicity. Although the pharmacological activities and metabolism of koumine and gelsemine have been reported in previous studies, the species differences of gelsevirine metabolism have not been well studied. In this study, the metabolism of gelsevirine was investigated by using liver microsomes of humans, pigs, goats and rats by means of HPLC-QqTOF/MS. The results indicated that the metabolism of gelsevirine in liver microsomes had qualitative and quantitative species differences. Based on the results, the possible metabolic pathways of gelsevirine in liver microsomes were proposed. Investigation of the metabolism of gelsevirine will provide a basis for further studies of the in vivo metabolism of this drug.

| S-EPMC8464259 | biostudies-literature

In Vitro Metabolism of Donepezil in Liver Microsomes Using Non-Targeted Metabolomics.

Project description:Donepezil is a reversible acetylcholinesterase inhibitor that is currently the most commonly prescribed drug for the treatment of Alzheimer's disease. In general, donepezil is known as a safe and well-tolerated drug, and it was not associated with liver abnormalities in several clinical trials. However, rare cases of drug-related liver toxicity have been reported since it has become commercially available. Few studies have investigated the metabolic profile of donepezil, and the mechanism of liver damage caused by donepezil has not been elucidated. In this study, the in vitro metabolism of donepezil was investigated using liquid chromatography-tandem mass spectrometry based on a non-targeted metabolomics approach. To identify metabolites, the data were subjected to multivariate data analysis and molecular networking. A total of 21 donepezil metabolites (17 in human liver microsomes, 21 in mice liver microsomes, and 17 in rat liver microsomes) were detected including 14 newly identified metabolites. One potential reactive metabolite was identified in rat liver microsomal incubation samples. Metabolites were formed through four major metabolic pathways: (1) O-demethylation, (2) hydroxylation, (3) N-oxidation, and (4) N-debenzylation. This study indicates that a non-targeted metabolomics approach combined with molecular networking is a reliable tool to identify and detect unknown drug metabolites.

| S-EPMC8309179 | biostudies-literature

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes.

Project description:Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug-drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM) using metabolomic approaches. In human liver microsomes (HLM), we identified seven metabolites including one cysteine-sepin-1 adduct and one glutathione-sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 ?M but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 ?M. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.

| S-EPMC5949348 | biostudies-literature

Dataset from proteomic analysis of rat, mouse, and human liver microsomes and S9 fractions.

Project description:Rat, mouse and human liver microsomes and S9 fractions were analyzed using an optimized method combining ion exchange fractionation of digested peptides, and ultra-high performance liquid chromatography (UHPLC) coupled to high resolution tandem mass spectrometry (HR-MS/MS). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository (Vizcaíno et al., 2013 [1]) with the dataset identifiers PXD000717, PXD000720, PXD000721, PXD000731, PXD000733 and PXD000734. Data related to the peptides (trypsin digests only) were also uploaded to Peptide Atlas (Farrah et al., 2013 [2]) and are available with the dataset identifiers PASS00407, PASS00409, PASS00411, PASS00412, PASS00413 and PASS00414. The present dataset is associated with a research article published in EuPA Open Proteomics [3].

| S-EPMC4510096 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data