Abstract：
:Aflatoxin B1 (AFB1) is bioactivated by cytochrome P450 (CYP) 3A isoforms in humans to generate the highly reactive epoxide intermediate AFB1-8,9-epoxide (AFBO), causing hepatotoxicity and hepatocarcinoma. Due to the unavoidable contamination in their feed, pigs are more likely to be exposed to AFB1 and indirectly harm human health. Therefore, identifying the porcine CYP3A isoforms involved in AFB1-8,9-epoxidation is critical. In this study, we used codon optimization and N-terminal coding sequence modification to modify a CYP3A46 recombinant protein that exhibits good structure and catalytic activities and revealed its strong AFB1-8,9-epoxidase activity for the first time. Site-directed mutagenesis, kinetics and docking analyses were performed and demonstrated that residues Phe-108, Ser-119, Phe-215, Phe-304 and Thr-309 play important roles in AFB1-8,9-epoxidation and its responsiveness to α-naphthoflavone. Interestingly, we uncovered the dual and reverse roles of Phe-304 in CYP3A46, CYP3A5 and CYP3A4 in AFB1 oxidation. Unlike the π-π interaction between the Phe-304 phenyl of CYP3A4 and the AFB1 aromatic ring, Phe-304 of CYP3A46 may function to provide steric hindrance to bind AFB1. Phe-108 and Phe-215 could stabilize AFB1 with a potentially productive orientation through van der Waals interactions with AFB1. Ser-119 and Thr-309 are likely to function to form H-bonds with AFB1. This study broadens our knowledge of AFB1 bioactivation in pigs and may contribute to reduce the deleterious effects of AFB1 in pigs and humans.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Jiang H,Wu J,Zhang F,Wen J,Jiang J,Deng Ydoi
10.1016/j.bcp.2018.08.030subject
Has Abstractpub_date
2018-10-01 00:00:00pages
177-185eissn
0006-2952issn
1873-2968pii
S0006-2952(18)30356-3journal_volume
156pub_type
杂志文章abstract：:Free radical-induced damage to lipid and protein constituents of neuronal membranes contributes to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). The development of an effective inhibitor of oxidative stress represents an important goal for the treatment of AD. In this study, th...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(00)00374-9
更新日期：2000-09-01 00:00:00
abstract：:Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released from KS and host cells and HIV viral products-the protein Tat are reported to be involved in angiogenesis. Mounting evidence further suggests that m...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.06.012
更新日期：2007-11-01 00:00:00
abstract：:LLC-PK(1) is a proximal tubular cell line derived from normal pig kidney which has a structure and function similar to those of renal proximal tubular cells and which expresses baseline levels of P-glycoprotein. We isolated by drug selection a doxorubicin-resistant cell line (LLC-PK(1)/ADR) that exhibited a multidrug-...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(00)00535-9
更新日期：2001-01-01 00:00:00
abstract：:Acute respiratory distress syndrome threatens public health with high morbidity and mortality due to ineffective intervention whereby lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice provides a research model. The seeds of Euphorbia lathyris L. have a long history of usage in Traditional Chinese Medici...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2018.07.025
更新日期：2018-09-01 00:00:00
abstract：:The effect of cyclosporin A (CyA) on 2-deoxyglucose (2DG) uptake by soleus muscles of ICR mice was studied in vivo and in vitro. The basal and insulin-stimulated uptakes of 2DG by the muscles as well as the plasma insulin level were significantly decreased by the in vivo treatment of mice with 20 mg/kg/day of CyA for ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90202-t
更新日期：1992-04-01 00:00:00
abstract：:Taxol-induced mitotic block and apoptosis were investigated using taxol-sensitive human leukemia HL-60 cells at submicromolar concentrations of the drug. Cells exposed to either 20 nM taxol for 1 hr or 10 nM taxol for 12 hr were able to resume normal growth, whereas cells exposed to 60 nM taxol for 1 hr or 10 nM taxol...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(97)82450-1
更新日期：1997-06-01 00:00:00
abstract：:The mechanism by which p-chlorophenoxyisobutyric acid (clofibric acid) induces striking changes in the proportion of the molecular species of phosphatidylcholine (PC) in rat liver was studied. Treatment of rats with clofibric acid strikingly increased the content of 1-palmitoyl-2-oleoyl (16:0-18:1) PC, but decreased t...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(01)00735-3
更新日期：2001-10-01 00:00:00
abstract：:Vanadate (VO3-) was found to activate adenylyl cyclase (AC) in ocular ciliary process membrane. This response was additive to that of isoproterenol (ISO) and vasoactive intestinal peptide (VIP), but it was potentiative with forskolin (FSK) and also with Ca2+/calmodulin activation of AC activity. The potentiated respon...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90284-4
更新日期：1993-03-24 00:00:00
abstract：:Oxysterols possess anti-proliferative properties that may be used with much effect in the treatment of cancer. We have demonstrated previously that 7 beta-hydroxycholesterol (7b-HC) provokes both metabolic stress, as witnessed by AMPK activation, and changes in lipid raft composition in C6 glioblastoma cells. These ob...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2013.03.012
更新日期：2013-07-01 00:00:00
abstract：:The sulfated glycolipid PG545 shows promising antitumor activity in various cancers. This study was conducted to explore the effects and the mechanism of PG545 action in endometrial cancer (EC). PG545 exhibited strong synergy as assessed by the Chou-Talalay-Method in vitro when combined with cisplatin, or paclitaxel i...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2020.114003
更新日期：2020-08-01 00:00:00
abstract：:We investigated the mechanism of phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells focusing on the p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (Hsp27) pathway. PMA-induced cell migration and activation of p38MAPK in A172 glioblastoma cells. PMA-induced formation of lam...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.06.018
更新日期：2007-09-01 00:00:00
abstract：:We reported previously that the flavoprotein inhibitor diphenyleneiodonium sulfate (DPI) irreversibly inhibited the metabolic activation of glyceryl trinitrate (GTN) in isolated aorta, possibly through inhibition of vascular NADPH-cytochrome P450 reductase (CPR). We report that the content of CPR represents 0.03 to 0....
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(98)00216-0
更新日期：1998-10-01 00:00:00
abstract：:The intraperitoneal injection of methylglyoxal bis(cyclohexylamidinohydrazone) (MGBC), an inhibitor of S-adenosylmethionine decarboxylase and spermidine synthase, markedly increased (7-fold of the basal level at 4 hr) ornithine decarboxylase (ODC) activity in normal mouse liver. ODC activity was also increased 2.5-fol...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(88)90104-9
更新日期：1988-11-01 00:00:00
abstract：:The substrate specificity of highly purified pig liver catechol-O-methyltransferase has been investigated kinetically. This enzyme shows stereospecificity towards the naturally occurring L-isomer of 3,4-dihydroxyphenylalanine (DOPA) which has a higher affinity and maximal velocity as a substrate than the D-form. We ha...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90194-0
更新日期：1982-02-01 00:00:00
abstract：:It has been suggested that vasoactive intestinal polypeptide (VIP) has a role as a neurotransmitter and that it participates in the control of hormone release from thyroid follicles. Many hormones and neurotransmitters alter the ionic permeability properties of the plasma membrane of their target cells when they bind ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90671-x
更新日期：1987-12-15 00:00:00
abstract：:Oridonin is a diterpene compound that regulates the activity of PPAR-γ (peroxisome proliferator-activated receptor gamma) transcription factor. Cumulative evidence indicates that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) play an important role in the treatment of de...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2020.114136
更新日期：2020-10-01 00:00:00
abstract：:The tissue distribution of captopril, an antihypertensive drug possessing a free sulfhydryl group, and its sulfur-conjugated metabolites was studied in rats by gas chromatography-mass spectrometry at 15, 30 and 60 min following a single 10 mg/kg oral dose of captopril. It was found that tissue accumulation of captopri...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(83)90328-3
更新日期：1983-05-15 00:00:00
abstract：:The mechanism of the antiaggregating activity of flavonoids was studied in vitro. The activity of fifteen different compounds was tested on platelet aggregation and arachidonic acid metabolism. The effect of flavonoids on platelet adenosine 3',5'-cyclic monophosphate (cyclic AMP) levels under basal conditions, as well...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90423-4
更新日期：1984-05-01 00:00:00
abstract：:(1) As a first step in studying the kinetics of the lipolytic system of rat adipocytes, the day-to-day variation between dose-response curves has been analysed. (2) Methods are described for the evaluation of large quantities of data relating noradrenaline to lipolysis. (3) A 'clustering' technique is presented which ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90455-5
更新日期：1982-03-01 00:00:00
abstract：:Auranofin (AF) is a newly introduced oral gold compound having antirheumatic properties, and its efficacy in the treatment of bronchial asthma is now under investigation. In this study, we examined the effects of AF on leukotriene (LT) formation by human polymorphonuclear leukocytes (PMNs) stimulated with the calcium ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90113-4
更新日期：1987-05-01 00:00:00
abstract：:The carboxylesterase activity in both plasma and liver of guinea-pig were separated into three main peaks by chromatofocusing. Two of the three plasma enzymes were retained by affinity chromatography on Affi-Gel Blue (100-200 mesh). Isoelectric points determined by chromatofocusing or isoelectrofocusing were pI 6.1, p...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(87)90461-8
更新日期：1987-11-15 00:00:00
abstract：:Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2013.01.015
更新日期：2013-04-15 00:00:00
abstract：:The present study investigated the presence of ryanodine receptors in the trematode Schistosoma mansoni. [3H]Ryanodine specific binding sites were found in the four subcellular fractions of S. mansoni; however, more binding sites were recovered in the heterogeneous fraction P1 and the microsomal fraction P4, as was th...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(98)00219-6
更新日期：1998-10-15 00:00:00
abstract：:Glutathione conjugation and transportation of glutathione conjugates of anticancer drugs out of cells are important for detoxification of many anticancer drugs. Inhibition of this detoxification system has recently been proposed as a strategy to treat drug-resistant solid tumors. Gallbladder carcinoma is resistant to ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2009.12.006
更新日期：2010-04-15 00:00:00
abstract：:The aspirin esterase activity of human plasma is due to butyrylcholinesterase and albumin. Our goal was to identify the amino acid residues involved in the aspirin esterase activity of albumin. Fatty acid-free human albumin and human plasma were treated with aspirin for 5 min-24 h. Acetylated residues were identified ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2009.10.007
更新日期：2010-03-01 00:00:00
abstract：:Indole-3-carbinol (I3C), found in cruciferous vegetables, has been shown to suppress tumorigenesis at estrogen-responsive sites. This effect may be mediated through modification by I3C of the cytochrome P450 (CYP) complement and activities leading to estrogen detoxication. In this study, we examined the effects of 4- ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(02)01190-5
更新日期：2002-08-01 00:00:00
abstract：:Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases that play a critical role in the destruction of extracellular matrix proteins and, the shedding of membrane-bound receptor molecules ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2019.02.033
更新日期：2019-07-01 00:00:00
abstract：:The multidrug resistance (MDR) phenotype is the major cause of failure of cancer chemotherapy. This phenotype is mainly due to the overexpression of the human MDR1 (hMDR1) gene. Several studies have shown that transcriptional regulation of this gene is unexpectedly complex and is far from being completely understood. ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/s0006-2952(02)01156-5
更新日期：2002-09-01 00:00:00
abstract：:Surfaces of higher eukaryotes such as plants, invertebrates, and vertebrates, including humans, are normally covered with microorganisms but usually are not infected by them. The reason, apart from physical barriers, is the production of gene-encoded antimicrobial peptides by epithelial cells. Many novel antimicrobial...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/s0006-2952(98)00226-3
更新日期：1999-01-15 00:00:00
abstract：:The fallen concentration of one of the two isomers of soman (1,2,2-trimethylpropyl methylphosphonofluoridate), i.e., C(+)P(-)-soman, was investigated in plasma and in homogenates of brain, lung, liver, kidney, diaphragm, skeletal muscle and mucosa of small intestines from rat, guinea pig and marmoset, and in human pla...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90106-7
更新日期：1993-10-19 00:00:00
