Abuse of synthetic cannabinoids (SCs), such as [1-naphthalenyl-(1-pentyl-1<i>H</i>-indol-3-yl]-methanone (JWH-018) and [1-(5-fluoropentyl)-1<i>H</i>-indol-3-yl]-1-naphthalenyl-methanone (AM2201), is increasing at an alarming rate. Although very little known about the metabolism toxicology these popular designer drugs, mass spectrometric analysis human urine specimens after JWH-018 AM2201 exposure identified monohydroxylated carboxylated derivatives major metabolites. The present study...

Tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive ingredient in marijuana, is subject to cytochrome P450 oxidation and subsequent UDP-glucuronosyltransferase (UGT)-dependent glucuronidation. Many studies have shown that CYP2C9 CYP3A4 are enzymes responsible for these P450-dependent oxidations, but little work has been done characterize phase II metabolic pathways. In this study, we test hypothesis there specific human UGTs classic cannabinoid metabolism. The activities of 12...

K2, a synthetic cannabinoid (SC), is an emerging drug of abuse touted as "legal marijuana" and marketed to young teens first-time users. Symptoms associated with K2 use include extreme agitation, syncope, tachycardia, visual auditory hallucinations. One major challenge clinicians the lack clinical, pharmacological, metabolic information for detection characterization its metabolites in human samples. Information on pathway SCs very limited. However, previous reports have shown these...

ABSTRACT Graphene and single‐walled carbon nanotubes were used to deliver the natural low‐toxicity drug gambogic acid (GA) breast pancreatic cancer cells in vitro , effectiveness of this complex suppressing cellular integrity was assessed. Cytotoxicity assessed by measuring lactate dehydrogenase release, mitochondria activity, mitochondrial membrane depolarization, DNA fragmentation, intracellular lipid content, permeability/caspase activity. The nanomaterials showed no toxicity at...

Rationale. The therapeutic promise of trans-resveratrol (tRes) is limited by poor bioavailability following rapid metabolism. We hypothesise that trans-arachidin-1 (tA1) and trans-arachidin-3 (tA3), peanut hairy root-derived isoprenylated analogs tRes, will exhibit slower metabolism/enhanced retain biological activity via cannabinoid receptor (CBR) binding relative to their non-prenylated parent compounds trans-piceatannol (tPice) respectively.Results. activities eight human...

The human UDP-glucuronosyltransferase (UGT) subfamily 1A includes nine genes. expression of all the UGT1A isoforms, apart from UGT1A5, has been reported previously. We have now detected a low basal level UGT1A5 in cultured hepatocytes, and treatment with rifampicin or 3-methylcholanthrene increased mRNA. Low-level was also found HepG2 Caco-2 cells as well liver. Furthermore, various segments intestine donors, revealing high interindividual variability its distribution along intestine....

Human UDP-glucuronosyltransferase (UGT) 2B7 is the major isoform catalyzing glucuronidation of a variety endogenous compounds including bile acids. To determine role acids in regulation UGT2B7 expression, Caco-2 cells were incubated with natural human farnesoid X receptor (hFXR) ligand, chenodeoxycholic acid, as well secondary lithocholic derived from acid. Incubation acid absence exogenous hFXR resulted dose-dependent down-regulation <i>UGT2B7</i> mRNA levels, an IC₅₀ 13 μM....

Arachidonic acid (AA) can be metabolized to various metabolites, which act as mediators of cellular processes. The objective this work was identify whether AA, prostaglandin (PG) B₁ and E₂, 15- 20-hydroxyeicosatetraenoic acids (15- 20-HETE) are via glucuronidation. Assays with human recombinant UDP-glucuronosyltransferase 1A (UGT1A) isoforms revealed that AA 15-HETE were glucuronidated by UGT1A1, 1A3, 1A4, 1A9, 1A10, whereas 20-HETE UGT1A1 1A4 PGB₁ 1A10. All...

4-Azido-2-hydroxybenzoic acid (4-AzHBA), a novel photoactive benzoic derivative, has been synthesized and used as photoprobe to identify the phenol binding site of UDP-glucuronosyltransferases (UGTs). Analysis recombinant His-tag UGTs from 1A family for their ability glucuronidate p-nitrophenol (pNP) 4-methylumbelliferone (4-MU) revealed that UGT1A10 shows high activity toward phenols derivatives. Purified was photolabeled with 4-AzHBA, digested trypsin, analyzed by matrix-assisted laser...

Our understanding of human phase II metabolic pathways which facilitate detoxification and excretion warfarin (Coumadin) is limited. The goal this study was to test the hypothesis that there are specific hepatic extrahepatic UDP-glucuronosyltransferase (UGT) isozymes, responsible for conjugating hydroxylated metabolites warfarin. Glucuronidation activity liver microsomes (HLMs) eight recombinant UGTs toward (<i>R</i>)- (<i>S</i>)-warfarin, racemic warfarin, major cytochrome P450 (4′-, 6-,...

Advances in anticancer chemotherapy have been hindered by the lack of biocompatibility new prospective drugs. One significant challenge concerns water insolubility, which compromises bioavailability drugs leading to increased dosage and higher systemic toxicity. To overcome these problems, nanodelivery has established as a promising approach for increasing efficacy lowering required chemotherapeutics. The naturally derived compound, parthenolide (PTL), is known its anti-inflammatory...

Increased aerobic glycolysis and de novo lipid biosynthesis are common characteristics of invasive cancers. UDP-glucuronosyltransferases (UGTs) phase II drug metabolizing enzymes that in normal cells possess the ability to glucuronidate these lipids speed their excretion; however, de-regulation cancer can lead an accumulation bioactive lipids, which further fuels progression. We hypothesize UGT2B isoform expression is down-regulated exogenous re-introduction will reduce content, change...

5-Diethylaminoethylamino-8-hydroxyimidazoacridinone, C-1311 (NSC-645809), is an antitumor agent shown to be effective against breast cancer in phase II clinical trials. A similar compound, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, shows high activity experimental tumors and expected have even more beneficial pharmacological properties than C-1311. Previously published studies showed that these compounds are not substrates for cytochrome P450s; however, they do contain...

Coumadin (<i>R</i>-, <i>S</i>-warfarin) is a challenging drug to accurately dose, both initially and for maintenance, because of its narrow therapeutic range wide interpatient variability typically administered as racemic (Rac) mixture, which complicates the biotransformation pathways. The goal current work was identify human UDP-glucuronosyltransferases (UGTs) involved in glucuronidation separated <i>R</i>- <i>S</i>-enantiomers 6-, 7-, 8-hydroxywarfarin possible interactions between these...

All UDP-glucuronosyltransferase enzymes (UGTs) share a common cofactor, UDP-glucuronic acid (UDP-GlcUA). The binding site for UDP-GlcUA is localized to the C-terminal domain of UGTs on basis amino sequence homology analysis and crystal structures glycosyltransferases, including human UGT2B7. We hypothesized that ³⁹³DQMDNAK³⁹⁹ region UGT1A10 interacts with glucuronic moiety UDP-GlcUA. Using site-directed mutagenesis enzymatic analysis, we demonstrated D393A mutation...

Trans-Resveratrol (tRes) has been shown to have powerful antioxidant, anti-inflammatory, anticarcinogenic, and antiaging properties; however, its use as a therapeutic agent is limited by rapid metabolism into conjugated forms UDP-glucuronosyltransferases (UGTs). The aim of the current study was test hypothesis that bioavailability tRes can be improved modifying structure create analogs which would glucuronidated at lower rate than itself. In this work, three synthetic stilbenoids,...

Tamoxifen (Tam) is a selective estrogen receptor modulator used to inhibit breast tumor growth. Tam can be directly <i>N</i>-glucuronidated via the tertiary amine group or <i>O</i>-glucuronidated after cytochrome P450–mediated hydroxylation. In this study, glucuronidation of and its hydroxylated and/or chlorinated derivatives [4-hydroxytamoxifen (4OHTam), toremifene (Tor), 4-hydroxytoremifene (4OHTor)] was examined using recombinant human UDP-glucuronosyltransferases (UGTs) from 1A subfamily...

Recent studies show that the extrahepatic human UDP-glucuronosyltransferase (UGT)1A10 is capable of phase II glucuronidation several major cytochrome P450 metabolites warfarin (i.e., 6-, 7-, and 8-hydroxywarfarin). This study expands on this finding by testing hypothesis UGT1A10 F⁹⁰-M⁹¹-V⁹²-F⁹³ amino acid motif important for proper recognition conjugation hydroxywarfarin derivatives. Site-directed mutagenesis demonstrate F⁹⁰ critical 6-...