Abstract:
:The leaves of the Mitragynine speciosia tree (also known as Kratom) have long been chewed, smoked, or brewed into a tea by people in Southeastern Asian countries, such as Malaysia and Thailand. Just this past year, the plant Kratom gained popularity in the United States as a "legal opioid" and scheduling it as a drug of abuse is currently pending. The primary alkaloid found in Kratom is a μ-opioid receptor agonist, mitragynine, whose structure contains a promising scaffold for immunopharmacological use. Although Kratom is regarded as a safe opioid alternative, here we report the LD50 values determined for its two main psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, as comparable to heroin in mice when administered intravenously. Given Kratom's recent emergence in the U.S., there is currently no diagnostic test available for law enforcement or health professionals, so we sought to design such an assay. Mitragynine was used as a starting point for hapten design, resulting in a hapten with an ether linker extending from the C9 position of the alkaloid. Bacterial flagellin (FliC) was chosen as a carrier protein for active immunization in mice, yielding 32 potential monoclonal antibodies (mAbs) for assay development. Antimitragynine mAbs in the range of micro- to nanomolar affinities were uncovered and their utility in producing a convenient lateral flow detection assay of human fluid samples was examined. Antibodies were screened for binding to mitragynine, 7-hydroxymitragynine, and performance in lateral flow assays. Two monoclonal antibodies were subcloned and further purified with 93 and 362 nM affinity to mitragynine. Test strip assays were optimized with a detection cut off of 0.5 μg/mL for mitragynine in buffer and urine (reflecting projected clinically relevant levels of drug in urine), which could be beneficial to law enforcement agencies and health professionals as the opioid epidemic in America continues to evolve.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Smith LC,Lin L,Hwang CS,Zhou B,Kubitz DM,Wang H,Janda KDdoi
10.1021/acs.chemrestox.8b00218subject
Has Abstractpub_date
2019-01-22 00:00:00pages
113-121issue
1eissn
0893-228Xissn
1520-5010journal_volume
32pub_type
杂志文章abstract::Basic research, exploring the hypothesis that 2-(ω-carboxyethyl)pyrrole (CEP) modifications of proteins are generated nonenzymatically in vivo is delivering a bonanza of molecular mechanistic insights into age-related macular degeneration, autism, cancer, and wound healing. CEPs are produced through covalent modificat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx200206v
更新日期:2011-11-21 00:00:00
abstract::Lesion-induced thermodynamic destabilization is believed to facilitate β-hairpin intrusion by the human XPC/hHR23B nucleotide excision repair (NER) recognition factor, accompanied by partner-base flipping, as suggested by the crystal structure of the yeast orthologue (Min, J. H., and Pavletich, N. P. (2007) Nature 449...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx1003613
更新日期:2010-12-20 00:00:00
abstract::Tetrabromobisphenol A, a brominated flame retardant, is increasingly prevalent worldwide and presents a potential health risk. Adjusted animal biomonitoring equivalents of tetrabromobisphenol A after orally administered doses in humanized-liver mice were scaled up to humans using known species allometric scaling facto...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00358
更新日期:2020-11-16 00:00:00
abstract::To investigate the biological effects of the O(2)-alkylthymidines induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), we have replicated a plasmid containing O(2)-methylthymidine (O(2)-Me-dT) or O(2)-[4-(3-pyridyl-4-oxobut-1-yl]thymidine (O(2)-POB-dT) in Escherichia coli w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200435d
更新日期:2011-11-21 00:00:00
abstract::The environmental contaminant benzo[c]phenanthrene (B[c]Ph) has weak carcinogenic activity in rodent bioassays; however, the fjord region diol epoxides of B[c]Ph, B[c]Ph-3,4-diol 1,2-epoxides (B[c]PhDE), are potent carcinogens. To determine the role of cytochrome P450 isozymes in the activation of B[c]Ph in MCF-7 cell...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960174n
更新日期:1997-05-01 00:00:00
abstract::Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300075j
更新日期:2012-10-15 00:00:00
abstract::We propose here a combined gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) metabolic profiling strategy to elucidate the toxicity in rats induced by orally administered multiglycosides of Tripterygium wilfordii Hook. f. (GTW) in multiple organs including the kidney, liv...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx7002905
更新日期:2008-02-01 00:00:00
abstract::On the basis of a large number of reports concerning the detection of lipid peroxidation products as biomarkers in human diseases, there is no doubt that their steady-state levels increase under pathophysiological states associated with oxidative stress. The key question is whether they play any causative roles. This ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx600304n
更新日期:2007-01-01 00:00:00
abstract::Pesticide biotransformation, especially by cytochrome P450 enzymes (CYPs), may produce metabolites with substantially altered toxicological and physicochemical profiles, which has drawn great attention as a basis for environmental risk assessment. CYPs are active in the metabolism of various reactions of pesticides, a...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00013
更新日期:2020-06-15 00:00:00
abstract::Rutaevin is one of the major bioactive constituents isolated from Evodia rutaecarpa, a well-known herbal medicine that has been widely prescribed for the treatment of gastrointestinal disorders in China. However, oral administration of rutaevin has been shown to cause hepatotoxicity in mice. Bioactivation was suggeste...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00475
更新日期:2020-12-21 00:00:00
abstract::The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is detoxified mainly by aldehyde dehydrogenase (ALDH). We find that the fungicide benomyl potently and rapidly inhibits ALDH and builds up DOPAL in vivo in mouse striatum and in vitro in PC12 cells and human cultured fibroblasts and glial cells. The in vi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx5002223
更新日期:2014-08-18 00:00:00
abstract::In humans and mice, in utero exposure to inorganic arsenic (iAs) is associated with adverse health outcomes later in life. The contribution of preconception exposure to the adverse outcomes in offspring has never been studied. Here combined in utero and postnatal exposures produce insulin resistance in two collaborati...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00107
更新日期:2019-08-19 00:00:00
abstract::Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population, above 65 years of age. Multiple lines of evidence confirm the central role of 40-42 residue Abeta peptides in the pathogenesis of AD, but exact mechanisms of Abeta toxicity remain unclear. Recently, evidence has accumulat...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900358j
更新日期:2010-02-15 00:00:00
abstract::Acyl glucuronides (AGs) are reactive metabolites of carboxylic acid-containing drugs, which are associated with idiosyncratic toxicity (IDT) such as anaphylaxis, drug-induced liver injury, and so on. In this study, we developed a new in vitro approach for the quantitative assessment of the reactivity of AGs and their ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00111
更新日期:2019-10-21 00:00:00
abstract::Catalase is an important antioxidant enzyme, which has been shown to provide cardiac protection from acute toxicity induced by doxorubicin, a most effective anticancer agent. Because cumulative dose-dependent chronic cardiomyopathy due to a long-term administration of doxorubicin is a significant clinical problem, the...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx015532n
更新日期:2002-01-01 00:00:00
abstract::Two 2-aminofluorene-derived hydroxamic acids that differ only in the nature of the N-acyl group were examined for their relative abilities to undergo covalent binding to nucleic acids. Studies of the bioactivation of N-hydroxy-N-acetyl-2-aminofluorene (N-OH-AAF) and N-hydroxy-N-glycolyl-2-aminofluorene (N-OH-GAF) were...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00001a008
更新日期:1988-01-01 00:00:00
abstract::The issue of the safety of drug metabolites in humans is a complex one. In this commentary, a proposal is made regarding how to deal with drug metabolites observed in humans such that the safety of these molecules can be assured. The human radiolabeled ADME study, in which metabolites are identified and quantified in ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0602012
更新日期:2006-12-01 00:00:00
abstract::The mechanism of aromatic hydroxylation of estrogens by cytochrome P450 enzymes has been examined by comparing the oxidation of estrone with that of substrates carrying additional aromaticity such as equilenin and the structural analog 2-naphthol. Hamster liver microsomes preferentially catalyzed the conversion of est...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970021f
更新日期:1997-07-01 00:00:00
abstract::The nuclear receptor human pregnane X receptor (hPXR) is a ligand-regulated transcription factor that responds to a wide range of endogenous and xenobiotic molecules. Upon activation with ligands, hPXR can increase induction levels of metabolic enzymes. Therefore, hPXR plays a critical role in drug metabolism and excr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200310j
更新日期:2011-10-17 00:00:00
abstract::Raloxifene (Evista) is a second generation selective estrogen receptor modulator used in the treatment of osteoporosis and for chemoprevention of breast cancer. It is bioactivated to reactive intermediates, which covalently bind to proteins and form GSH conjugates upon incubation with NADPH and GSH-supplemented human ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800323w
更新日期:2008-12-01 00:00:00
abstract::With CO2 present in excess, ONOO- reacts to form an adduct in solution and in the solid state, most likely ONOOCO2-. In solution, the adduct appears within 2 ms and absorbs at 300 with an extinction coefficient, which is either 50% or 100% (preferred) of that of ONOO-, 1.70 × 103 M-1 cm-1, and at 685 nm with an extinc...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00068
更新日期:2018-08-20 00:00:00
abstract::Among the cellular components that can react directly with peroxynitrite in the presence of physiological CO(2) concentrations are sulfur-, selenium-, and metal-containing proteins, in particular hemoproteins. We have previously shown that the reactions of peroxynitrite with oxymyoglobin (MbFeO(2)) and oxyhemoglobin p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx025595l
更新日期:2003-03-01 00:00:00
abstract::Lapatinib (LAP), an oral tyrosine kinase inhibitor for the treatment of metastatic breast cancer, has been associated with idiosyncractic hepatotoxicity. Recent investigations have implicated the importance of P450 3A4/5 enzymes in the formation of an electrophilic quinone imine (LAPQI) metabolite generated through fu...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00524
更新日期:2016-05-16 00:00:00
abstract::Mitomycin C (MMC) is a genotoxic cancer chemotherapeutic agent that reacts principally at the N2 position of guanine to form one of two predominant monoadducts, or a G-G interstrand cross-link at CpG sites, or a G-G intrastrand cross-link at GpG sites. Previous studies of MMC adduction have principally used very short...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960070c
更新日期:1996-10-01 00:00:00
abstract::The Salmonella typhimurium (TA100) mutagenic compound, mucochloric acid [3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA)], was inactivated by in vitro N-acetylcysteine (NAC). The reaction of MCA with NAC at pH7 was second order and gave products 4, 5, and 6a that resulted from the displacement of chlorine from C-3 or C-4 ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00029a005
更新日期:1992-09-01 00:00:00
abstract::Thiol conjugates of isothiocyanates (thiol-ITCs) are metabolites of ITCs formed in the mercapturic acid pathway in mammals. They are effective chemopreventive agents in mouse lung tumor bioassays and in other models. Thiol-ITCs are inhibitors of P450s, but it has not been determined if P450 inhibition is due to conjug...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010029w
更新日期:2001-09-01 00:00:00
abstract::The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected N-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have le...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960063o
更新日期:1996-09-01 00:00:00
abstract::We have reported [Correia et al. (1987) Arch. Biochem. Biophys. 258, 436-443] that administration of 3,5-dicarbethoxy-4-ethyl-2,6-dimethyl-1,4-dihydropyridine (DDEP) to untreated, phenobarbital (PB) pretreated, or dexamethasone (DEX) pretreated rats results in relatively selective inactivation of cytochrome P-450 (P-4...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00012a008
更新日期:1989-11-01 00:00:00
abstract::Dysregulation in the expression of microRNAs (miRNAs), single-stranded RNAs which regulate gene expression, has been associated with diseases such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), although their cellular origin has not been explored. Thus, the focus of this work was to study expressi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.7b00330
更新日期:2018-06-18 00:00:00
abstract::Electrochemical oxidation of drug molecules is a useful tool to generate several different types of metabolites. In the present study we developed a model system involving electrochemical oxidation followed by characterization of the oxidation products and their propensity to modify peptides. The CB1 antagonist rimona...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500255r
更新日期:2014-10-20 00:00:00