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5 results on '"SULT, sulfotransferase"'

1. The gut microbiome: an orchestrator of xenobiotic metabolism

Author

Stephanie L. Collins and Andrew D. Patterson

Subjects
Enterohepatic circulation, BDE, bromodiphenyl ether, ER, estrogen receptor, GUDCA, glycoursodeoxycholic acid, Microbial metabolism, PCB, polychlorinated biphenyl, Review, SCFA, short chain fatty acid, PD, Parkinson's disease, chemistry.chemical_compound, 0302 clinical medicine, Gastrointestinal tract, NSAID, non-steroidal anti-inflammatory drug, General Pharmacology, Toxicology and Pharmaceutics, 0303 health sciences, cgr, cytochrome glycoside reductase, PXR, pregnane X receptor, BRV, brivudine, CAR, constitutive androgen receptor, CV, conventional, TCDF, 2,3,7,8-tetrachlorodibenzofuran, Cell biology, 030220 oncology & carcinogenesis, CYP, cytochrome P450, PAH, polycyclic aromatic hydrocarbon, SULT, sulfotransferase, SN-38G, SN-38 glucuronide, Biology, BVU, bromovinyluracil, Absorption, 03 medical and health sciences, FXR, farnesoid X receptor, TUDCA, tauroursodeoxycholic acid, Detoxification, Pharmacokinetics, Microbiome, Transcription factor, 030304 developmental biology, Gut microbiome, Bioactivation, UGT, uracil diphosphate-glucuronosyltransferase, lcsh:RM1-950, PABA, p-aminobenzenesulphonamide, PFOS, perfluorooctanesulfonic acid, Metabolism, Xenobiotic metabolism, GF, germ-free, ALDH, aldehyde dehydrogenase, lcsh:Therapeutics. Pharmacology, chemistry, 5-ASA, 5-aminosalicylic acid, AHR, aryl Hydrocarbon Receptor, 5-FU, 5-fluorouracil, Xenobiotic, Drug metabolism
Abstract

Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut via enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell–cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism., Graphical abstract Xenobiotic metabolism and gut microbiome are tightly interconnected. This review highlights major interactions between the gut microbiome, host and xenobiotic that alter xenobiotic metabolism, with a focus on therapeutic drugs. Notably, a xenobiotic's outcome is altered by the gut microbiome directly metabolizing and/or indirectly perturbing host absorption and xenobiotic metabolism.Image 1

Published
2020

2. Small-molecule control of neurotransmitter sulfonation

Author

Alexander Deiters, Thomas S. Leyh, Ting Wang, Kristie Darrah, Ian Cook, and Mary Cacace

Subjects
Sulfotransferase, 1-HP, 1-hydroxypyrene, sulfotransferase, MDD, major depressive disorder, Biochemistry, allosteric, chemistry.chemical_compound, Catecholamines, DOPAC, 3,4-dihydroxyphenylacetic acid, MEM, Minimum Essential Media, education.field_of_study, Neurotransmitter Agents, biology, Molecular Structure, SULT1A3, structure activity relationship, MD, molecular dynamics, Arylsulfotransferase, Cell biology, inhibitor, Enzyme inhibitor, catecholamine, Sulfotransferases, DPS, dopamine sulfate, Allosteric Site, Research Article, neurotransmitter, Gene isoform, DP, dopamine, Serotonin, Allosteric regulation, Population, SULT, sulfotransferase, Molecular Dynamics Simulation, GST, glutathione sepharose, Structure-Activity Relationship, PAPS, 3′-phosphoadenosine 5′-phosphosulfate, Extracellular, HVA, homovanillic acid, Humans, education, Molecular Biology, Depressive Disorder, Major, HME, human mammary epithelial, 3-MT, 3-methoxytyramine, Epithelial Cells, Cell Biology, In vitro, molecular dynamics, human mammary epithelial cells, 3'-Phosphoadenosine-5'-phosphosulfate, Tam, 4-hydroxy-tamoxifen, Kinetics, chemistry, DTT, dithiothreitol, biology.protein, PAP, 3′-phosphoadenosine-5′-phosphate
Abstract

Controlling unmodified serotonin levels in brain synapses is a primary objective when treating major depressive disorder - a disease that afflicts ~20% of the world's population. Roughly 60% of patients respond poorly to first-line treatments and thus new therapeutic strategies are sought. Toward this end, we have constructed isoform-specific inhibitors of the human cytosolic sulfotransferase 1A3 (SULT1A3) - the isoform responsible for sulfonating ~80% of the serotonin in extracellular brain fluid. The inhibitor design includes a core ring structure, which anchors the inhibitor into a SULT1A3-specific binding pocket located outside the active site, and a sidechain crafted to act as a latch to inhibit turnover by fastening down the SULT1A3 active-site cap. The inhibitors are allosteric, they bind with nanomolar affinity and are highly specific for the 1A3 isoform. The cap-stabilizing effects of the latch can be accurately calculated and are predicted to extend throughout the cap and into the surrounding protein. A free energy correlation demonstrates that the percent inhibition at saturating inhibitor varies linearly with cap stabilization - the correlation is linear because the rate-limiting step of the catalytic cycle, nucleotide release, scales linearly with the fraction of enzyme in the cap-open form. Inhibitor efficacy in cultured cells was studied using a human mammary epithelial cell line that expresses SULT1A3 at levels comparable to those found in neurons. The inhibitors perform similarly in ex vivo and in vitro studies; consequently, SULT1A3 turnover can now be potently suppressed in an isoform-specific manner in human cells.

Published
2020

3. Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2)

Author

Majer, B.J., Hofer, E., Cavin, C., Lhoste, E., Uhl, M., Glatt, H.R., Meinl, W., and Knasmüller, S.

Subjects
*DITERPENES, *HEPATOCELLULAR carcinoma, *CARCINOGENS, *DIMETHYLNITROSAMINE, *CYTOCHROME P-450, *DNA repair
Abstract

Abstract: Aim of the present experiments was to study the genotoxic effects of coffee diterpenoids, namely cafestol palmitate and a mix of cafestol and kahweol (C+K) in human derived hepatoma (HepG2) cells. Furthermore, we investigated the potential protective properties of these substances towards carcinogens contained in the human diet, namely N-nitrosodimethylamine (NDMA) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). C+K and cafestol palmitate were tested over a broad dose range in micronucleus (MN) assays and no indication for genotoxic effects was seen. In combination experiments with PhIP (300μM), pronounced inhibition (≈1.7-fold) of MN formation was observed with C+K and cafestol palmitate at dose levels ⩾0.9 and 1.7μg/ml, respectively. Enzyme measurements indicate that the protection is due to inhibition of sulfotransferase, an enzyme involved in the activation of the amine, and/or to induction of UDP-glucuronosyltransferase which detoxifies the DNA-reactive metabolites of PhIP. Furthermore, a significant increase of glutathione-S-transferase was seen, whereas the activities of cytochrome P-450 1A1 and N-acetyltransferase 1 were not significantly altered. Also in combination experiments with C+K and NDMA, strong protective effects (50% reduction of genotoxicity) were seen at low dose levels (⩾0.3μg/ml). Since inhibition of MN was also observed when C+K were added after incubation with NDMA, it is likely that the chemoprotective effects are due to induction of DNA repair enzymes. Comparison of data on the effects of C+K on the cholesterol metabolism, which was investigated in earlier in vivo studies, with the present findings suggests that DNA-protective effects take place at exposure levels which are substantially lower than those which cause hypercholesterolemia. [Copyright &y& Elsevier]

Published
2005
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4. The gut microbiome: an orchestrator of xenobiotic metabolism.

Author

Collins SL and Patterson AD

Abstract

Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut via enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2020
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5. Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine.

Author

Park S, Cheng SL, and Cui JY

Abstract

Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type and Car -/- mice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice, Car mRNA was down-regulated by TCPOBOP in liver and duodenum. Car -/- mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs ( Cyp2b10, Cyp3a11, Aldh1a1, Aldh1a7, Gsta1, Gsta4, Gstm1-m4, Gstt1, Ugt1a1, Ugt2b34, Ugt2b36 , and Mrp2-4 ) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.

Published
2016
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