Abstract：
:Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24h after dosing, indicating that the major metabolic reactions encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ. In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ, and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity toward the PZQ enantiomers. Apparent Km and Vmax differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in substrate location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Wang H,Fang ZZ,Zheng Y,Zhou K,Hu C,Krausz KW,Sun D,Idle JR,Gonzalez FJdoi
10.1016/j.bcp.2014.05.001subject
Has Abstractpub_date
2014-07-15 00:00:00pages
166-78issue
2eissn
0006-2952issn
1873-2968pii
S0006-2952(14)00261-5journal_volume
90pub_type
杂志文章abstract：:OSI-7836 (4'-thio-araC, T-araC) is a nucleoside analogue that shows efficacy against solid tumor xenograft models. We examined how the triphosphates of OSI-7836 (T-araCTP), cytarabine (araCTP), and gemcitabine (dFdCTP) affected the initiation of new DNA strands by the pol alpha primase complex. Whereas dFdCTP very wea...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2004.07.042
更新日期：2004-12-15 00:00:00
abstract：:Thyroid hormones play a role in the regulation of glutathione S-transferase (GST) expression. Here, co-cultures of rat hepatocytes with bile duct epithelial cells have been used to study the direct effects of both triiodothyronine (T3) and thyroxine (T4) on GST activities and proteins. Because T3 and T4 are poorly wat...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(01)00557-3
更新日期：2001-05-01 00:00:00
abstract：:Naturally soluble rat germ cell adenylate cyclase was inhibited by adenosine and the adenosine analogs, 9-beta-D-arabinofuranosyl adenine (AFA) and 2',5'-dideoxyadenosine (DDA), all of which inhibited hormone-sensitive adenylate cyclases at the "P" site. The IC50 values for adenosine and DDA were approximately 0.1 and...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90487-4
更新日期：1987-06-15 00:00:00
abstract：:The effect of natural polyphenols on three isoforms of NO-synthase was investigated. Among the compounds tested, tannin was the most potent, inhibiting endothelial constitutive NO synthase (eNOS) with an IC50 of 2.2 microM. Other NOS isoforms (i.e. neuronal constitutive NOS and smooth muscle inducible NOS) were also i...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)00433-m
更新日期：1995-02-14 00:00:00
abstract：:Most in vivo studies demonstrating decreased activities of hepatic cytochromes P450 with inflammation have used Gram-negative bacterial lipopolysaccharide (LPS) as the inflammatory stimulant. But products of Gram-positive bacteria, such as staphylococcal enterotoxin B (SEB), also stimulate inflammatory mediators, albe...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(00)00250-1
更新日期：2000-05-15 00:00:00
abstract：:Human CYP2E1 is one of the pharmacologically and toxicologically important cytochrome P450 isoforms. Earlier studies have reported that the CYP2E1 expression is extensively regulated by post-transcriptional and post-translational mechanisms, but the molecular basis remains unclear. In the present study, we examined th...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2009.11.015
更新日期：2010-04-01 00:00:00
abstract：:Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation. HO regulates the cellular content of the pro-oxidant heme and produces catabolites with physiological functions. HO-1 is induced by a host of oxidative stress stimuli, and the activation of HO-1 gene expression is considere...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/s0006-2952(00)00443-3
更新日期：2000-10-15 00:00:00
abstract：:There is a strong association between tobacco smoking and the consumption of alcoholic beverages. When compared to the effects of either drug on its own, the combined use may lead to worsened outcomes, such as less successful quitting attempts and increased likelihood of developing mood disorders. Co-consumption most ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2017.06.113
更新日期：2017-11-15 00:00:00
abstract：:The activator protein-1 (AP-1) family of transcription factors, including the most common member c-Jun-c-Fos, participates in regulation of expression of numerous genes involved in proliferation, apoptosis, and tumorigenesis in response to a wide array of stimuli including pro-inflammatory cytokines, growth factors, s...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2006.07.007
更新日期：2006-10-16 00:00:00
abstract：:Retinoic acid isomers have been used with some success as chemotherapeutic agents, most recently with 13-cis retinoic acid showing impressive clinical efficacy in the paediatric malignancy neuroblastoma. The aim of this commentary is to review the evidence that 13-cis retinoic acid is a pro-drug, and consider the impl...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2005.02.003
更新日期：2005-05-01 00:00:00
abstract：:Sepsis is a complex clinical syndrome that results from a harmful host response to infection, in which foreign bacteria and lipopolysaccharide (LPS) are potent activators of different immune cells, including monocytes and macrophages. To date, there are currently few effective adjuvant therapies in clinical use except...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2005.04.040
更新日期：2005-07-15 00:00:00
abstract：:The effect of oxidant stress produced by redox cycling of substituted 1,4-naphthoquinones on the activity of platelet (Na(+)-K+)ATPase and the active transport of serotonin (5-HT) was studied. 2-Methyl-1,4-naphthoquinone (menadione) produced a concentration-dependent (0-100 microM) and time-dependent (2-20 min) stimul...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(91)90203-h
更新日期：1991-03-15 00:00:00
abstract：:When HL-60 cells were stimulated with histamine, a significant differentiation of the cells toward neutrophils was elicited. Histamine increased phagocytic activity, but it reduced myeloperoxidase activity of HL-60 cells. Histamine-induced differentiation in HL-60 cells was inhibited not only by H2 antagonists, such a...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90375-s
更新日期：1992-09-25 00:00:00
abstract：:The role of CYP2E1 in ketone-stimulated insulin release was investigated using isolated pancreatic islets of Langerhans and two mammalian insulin secreting pancreatic beta-cell lines engineered to stably express human CYP2E1 (designated BRIN BD11h2E1 and INS-1h2E1). Isolated rat pancreatic islets were shown to express...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2003.10.011
更新日期：2004-03-01 00:00:00
abstract：:Substituted fentanyls are abused and cause rapid fatal overdose. As their pharmacology is not well characterized, we examined in vitro pharmacology and structure-activity relationships of 22 substituted fentanyls with modifications of the fentanyl propyl group, and conducted in silico receptor/ligand modeling. Affinit...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2020.114293
更新日期：2020-12-01 00:00:00
abstract：:The abilities of the naturally occurring polyamines, putrescine, spermidine and spermine, to affect variables related to the bioenergetic functions of isolated rat liver mitochondria were studied. At concentrations comparable to those present intracellularly, the polyamines inhibited state 4 respiration, but they had ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90654-2
更新日期：1982-12-15 00:00:00
abstract：:Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine ch...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2015.06.001
更新日期：2015-08-01 00:00:00
abstract：:We compared the anti-proliferative properties of 4-benzylphenoxy-N ethyl morpholine (morpho-BPE) and trifluopromazine (TFP) on both the human breast cancer cell lines, MCF7, and its tamoxifen-resistant variant RTx6. We found that the calmodulin antagonist trifluopromazine (TFP) which bound ABS weakly, inhibited MCF7 c...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90539-w
更新日期：1990-08-01 00:00:00
abstract：:The effect of verapamil in a model system of A23187-induced Ca2+-uptake into liposomes was studied. This was done in order to separate the effects of verapamil on the lipid phase of membranes from its effects on membraneous proteins. In the absence of A23187, the liposomes exhibited a very low Ca2+ permeability, which...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90237-1
更新日期：1987-06-01 00:00:00
abstract：:Epothilones constitute a novel class of antitubulin agents that are active in patients who relapse after treatment with other chemotherapeutics. This study investigated the molecular mechanisms leading to the onset of epothilone-B (patupilone) resistance in ovarian cancer. Results demonstrated that the Gli family of t...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2012.08.019
更新日期：2012-12-01 00:00:00
abstract：:The inhibition of semicarbazide-sensitive amine oxidase (SSAO) in rat aorta homogenates by some 2-phenyl-3-haloallylamines has been studied. Derivatives containing a fluorine atom were approximately three times more potent than the corresponding 3-chloroallylamines. These halogen-containing compounds were irreversible...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90275-9
更新日期：1987-09-01 00:00:00
abstract：:Reduced glutathione is nitrosated in aerobic solutions of nitric oxide under physiological conditions; however, the extent of S-nitrosation was found to be dependent on the inorganic anions present. Of nine anions tested, the bifunctional anions, arsenate, phosphate, and pyrophosphate (40 mM), inhibited the S-nitrosat...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(96)00825-8
更新日期：1997-02-21 00:00:00
abstract：:The large amount of nitric oxide (NO) produced by inducible NO synthase (iNOS) contributes to cellular injury in inflammatory disease. In the present study, a novel synthetic compound (3E)-4-(2-hydroxyphenyl)but-3-en-2-one (HPB) was found to inhibit lipopolysaccharide (LPS)-induced NO generation, but not through the i...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2005.05.032
更新日期：2005-08-15 00:00:00
abstract：:PI3K cascade is a central signaling pathway regulating cell proliferation, growth, differentiation, and survival. Tight regulation of the PI3K signaling pathway is necessary to avoid aberrant cell proliferation and cancer development. Together with SHIP-1, the inositol phosphatases PTEN and SHIP-2 are the gatekeepers ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2011.05.031
更新日期：2011-11-15 00:00:00
abstract：:Agonist-stimulated phosphoinositide metabolism plays a central role in pharmacomechanical coupling in airways smooth muscle (ASM). In many other tissues and cells, most noteably excitable cells, membrane depolarization or an increase in intracellular Ca2+ ([Ca2+]i) generated by inositol 1,4,5-trisphosphate (Ins(1,4,5)...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90252-6
更新日期：1994-06-15 00:00:00
abstract：:Neutrophil serine proteases (NSPs), including elastase, proteinase 3 and cathepsin G, play critical roles in the pathogenesis of chronic inflammatory lung diseases. The release of excess NSPs leads to the destruction of lung tissue and an overexuberant, sustained inflammatory response. Antiproteases could be valuable ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2012.03.009
更新日期：2012-06-15 00:00:00
abstract：:The present study describes the isolation of the first neurotoxin (acantoxin IVa) from Acanthophis sp. Seram death adder venom and an examination of its activity at nicotinic acetylcholine receptor (nAChR) subtypes. Acantoxin IVa (MW 6815; 0.1-1.0 microM) caused concentration-dependent inhibition of indirect twitches ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2004.03.033
更新日期：2004-07-15 00:00:00
abstract：:Nitric oxide is an important mediator of excessive cell growth and inflammation associated with many epidermal proliferative disorders. It is a highly reactive oxidant generated in keratinocytes and macrophages via the inducible form of the enzyme nitric oxide synthase (NOS2). In the present studies, we examined the e...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(02)01419-3
更新日期：2002-11-15 00:00:00
abstract：:Alcohol-fed hamsters were used to study the mechanism by which acetaminophen initiates hepatotoxicity. Animals maintained on an ethanol-containing diet (Group B) exhibited an increased mortality rate after administration of acetaminophen (400 mg/kg) as compared to control hamsters (Group A). However, in those animals ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(83)90426-4
更新日期：1983-07-01 00:00:00
abstract：:Mitochondrial biogenesis is a key feature of energy expenditure and organismal energy balance. Genetic deletion of PARP1 or PARP2 was shown to induce mitochondrial biogenesis and energy expenditure. In line with that, PARP inhibitors were shown to induce energy expenditure in skeletal muscle. We aimed to investigate w...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2019.06.022
更新日期：2019-09-01 00:00:00
