Abstract:
:3 alpha-Hydroxysteroid dehydrogenase (EC 1.1.1.50) of rat liver cytosol catalyzes the second step in glucocorticoid metabolism, namely the NADPH-dependent reduction of 5 beta-dihydrocortisol to tetrahydrocortisol. The purified enzyme is potently inhibited by the nonsteroidal anti-inflammatory drugs [Penning and Talalay, Proc. natn. Acad. Sci. U.S.A. 80, 4504 (1983)], and the consequences of this inhibition on hepatic glucocorticoid metabolism are now examined. Analyses of the specific activities for the reduction of 5 beta-dihydro-cortisone catalyzed by homogeneous preparations of 3 alpha- and 3 beta-hydroxysteroid dehydrogenases of rat liver cytosol indicated that this steroid was predominantly reduced to the 3 alpha-hydroxysteroid (tetrahydrocortisone). Whether this reaction was catalyzed by the purified 3 alpha-hydroxysteroid dehydrogenase or unprocessed cytosol, it was potently inhibited by indomethacin (IC50 = 0.6 microM). In the presence of 30 microM indomethacin, the rate of reduction of 5 beta-dihydro-glucocorticoids was 16 times smaller than in the absence of drug. Measurement of 5 beta-reductase activity in rat liver cytosol indicated that it was 25-30 times less active than the 3 alpha-hydroxysteroid dehydrogenase. In the presence of 30 microM indomethacin, enough residual dehydrogenase may exist to reduce 5 beta-dihydro-glucocorticoids as they are formed. This was confirmed by incubating the supernatant fraction obtained from the 10,000 g centrifugation of a rat liver homogenate, with [1,2-3H]cortisol plus NADPH in the presence and absence of drug. At the end of the incubation, cortisol metabolites were analyzed by TLC and the results expressed as CL:CM ratio (cortisol left:cortisol metabolized). It was found that no change in this ratio occurred in the presence of the drug. Moreover, the addition of trapping quantities of 5 beta-dihydrocortisol to incubations containing 30 microM indomethacin were insufficient to promote an increase in cortisol levels as reflected by a rather small increase in the CL:CM ratio. Thus, nonsteroidal anti-inflammatory drugs cannot effect a rise in hepatic glucocorticoid levels in vitro, and do not promote a "glucocorticoid saving effect" in this organ.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Penning TMdoi
10.1016/0006-2952(86)90696-9subject
Has Abstractpub_date
1986-12-01 00:00:00pages
4203-9issue
23eissn
0006-2952issn
1873-2968pii
0006-2952(86)90696-9journal_volume
35pub_type
杂志文章abstract::Interferon and interferon inducers are well known to depress the cytochrome P450-dependent hepatic mixed-function oxidase system and cause a decrease in the capacity of the liver to metabolize drugs and xenobiotics. In this study we have shown that the interferon-mediated changes in an induced form of hepatic cytochro...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90458-u
更新日期:1992-08-04 00:00:00
abstract::The effects of two competitive antagonists and two allosteric ligands on the rate of dissociation of [3H]N-methylscopolamine ([3H]NMS) were studied at atrial muscarinic acetylcholine M2 receptors by the technique of "infinite dilution." The dissociation rate for [3H]NMS, initiated by diluting the incubation mixture in...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(96)00814-3
更新日期:1997-03-21 00:00:00
abstract::The aim of this study was to document the in vivo transport of everolimus (inhibitor of mTOR) by P-glycoprotein (P-gp), and to investigate the influence of lapatinib (inhibitor of P-gp) on everolimus disposition. Pharmacokinetics of everolimus (0.25mg/kg) has been investigated after oral administration in mdr1a-/1b- m...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.02.013
更新日期:2009-05-15 00:00:00
abstract::With the completion of the genome of Mycobacterium tuberculosis comes the promise of a new generation of potent drugs to combat the emerging epidemic of multiply drug-resistant isolates. Translating this genomic information into realistic assays, valid targets, and preclinical drug candidates represents the next great...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(99)00253-1
更新日期:2000-02-01 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::Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate β-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2021.114426
更新日期:2021-01-19 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::The O2 dependence of the metabolism of benzylamine to benzaldehyde, benzoate and hippurate was studied in isolated rat hepatocytes. The initial oxidation to benzaldehyde, catalyzed by monoamine oxidase, had an apparent Kmo2 value of 34 microM in cells and 40 microM in isolated rat liver mitochondria. The conversion of...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90234-x
更新日期:1984-02-01 00:00:00
abstract::The long-term effects of incubating freshly isolated, elicited guinea-pig peritoneal macrophages with the beta-adrenoceptor agonist isoprenaline and the selective inhibitor of phosphodiesterase (PDE) IV rolipram, on adenosine-3',5'-cyclic phosphate (cAMP)-specific PDE IV activity have been investigated. The level of c...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)02104-3
更新日期:1995-12-22 00:00:00
abstract::Despite tobacco being highly addictive, it is unclear if nicotine has significant affective properties. To address this, we studied taste reactions to gustatory stimuli, palatable sucrose and unpalatable quinine, which are believed to reflect ongoing affective state. Taste reactivity was assessed during chronic nicoti...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.06.017
更新日期:2009-10-01 00:00:00
abstract::Physiological levels of wild-type (wt) apolipoprotein E (apoE) in plasma mediate the clearance of cholesterol-rich atherogenic lipoprotein remnants while higher than normal plasma apoE concentrations fail to do so and trigger hypertriglyceridemia. This property of wt apoE reduces significantly its therapeutic value as...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2012.09.006
更新日期:2012-12-01 00:00:00
abstract::Vectorial secretion of cationic compounds across tubular epithelial cells is an important function of the kidney. This uni-directed transport is mediated by two cooperative functions, which are membrane potential-dependent organic cation transporters at the basolateral membranes and H+/organic cation antiporters at th...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2007.12.008
更新日期:2008-05-01 00:00:00
abstract::The actions of alkylating pindolol (N8-bromoacetyl-N1-3'-(4-indolyloxy)-2'-hydroxypropyl[z]-1,8- diamino-p-menthane; BIM) have been examined on beta-adrenoceptors in guinea-pig left atria and trachea. In organ bath experiments, addition of BIM (greater than or equal to 0.1 microM), followed by washout, produced concen...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90390-5
更新日期:1988-10-01 00:00:00
abstract::The deamination of 5-hydroxytryptamine, tryptamine and benzylamine by porcine dental pulp membrane preparations is brought about not only by monoamine oxidase, but also by a clorgyline (and deprenyl) resistant), semicarbazide sensitive enzyme. The semicarbazide sensitive enzyme was also inhibited by aminoguanidine, hy...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90127-7
更新日期:1982-09-01 00:00:00
abstract::The effect of deferoxamine on nucleotide metabolism in HL-60 leukemic cells was studied to explore the mechanism of its antiproliferation activity. It was found that in intact cells deferoxamine markedly inhibited the ribonucleotide reduction and incorporation of bases (adenine, hypoxanthine), ribonucleosides (inosine...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90601-0
更新日期:1987-07-15 00:00:00
abstract::Compounds of the mevalonate pathway containing a terminal di- or triphosphate (mev-PP or mev-PPP) were tested as substrates of several enzyme ligases (T4 RNA ligase, T4 DNA ligase, firefly luciferase and other ligases) for the synthesis of ATP derivatives of the mev-pppA or mev-ppppA type. T4 RNA ligase, in the presen...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.04.028
更新日期:2009-08-15 00:00:00
abstract::Ligand-receptor binding kinetics (i.e. association and dissociation rates) are emerging as important parameters for drug efficacy in vivo. Awareness of the kinetic behavior of endogenous ligands is pivotal, as drugs often have to compete with those. The binding kinetics of neurokinin 1 (NK1) receptor antagonists have ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2016.08.004
更新日期:2016-10-15 00:00:00
abstract::The effects of ticlopidine and six of its analogues on mitochondrial functions were studied in isolated rat liver mitochondria. The influence of ticlopidine and each of the following analogues: PCR 5325, PCR 4099, PCR 3787, PCR 2362, PCR 4499 and PCR 0665 was evaluated by determining their interaction with three major...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90057-1
更新日期:1984-12-01 00:00:00
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 ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2014.05.001
更新日期:2014-07-15 00:00:00
abstract::The inhibition of rat liver monoamine oxidase by a number of N-propargyl and alpha-methyl amine derivatives has been examined. The results indicate that alpha-methyl-substituted primary and secondary amine derivatives tend to show selectivity as reversible inhibitors towards the A-form of the enzyme. The structural fe...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90012-0
更新日期:1982-04-01 00:00:00
abstract::Nuclear factor-E2-related factor 2 (Nrf2) is a master transcription factor in antioxidant response, protecting against oxidative damage and various diseases. Previous studies suggest that Nrf2 is suppressed in fibrotic skin and Nrf2 agonists represent a therapeutic strategy, which is mainly attributed to Nrf2 function...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2020.113846
更新日期:2020-04-01 00:00:00
abstract::Daunorubicin (DNR) is a well known anticancer drug believed to act mainly by topoisomerase II inhibition and mitochondria-mediated free radical generation. Though several studies were dedicated to elucidate the mechanism of action of DNR, however the mechanism still remains illusive. DNR is reported to affect mitochon...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2007.06.009
更新日期:2007-09-15 00:00:00
abstract::The dissociation constant (Kd) for the binding of epinephrine to beta-adrenergic receptors of the S49 cell is 2 microM, which is the ratio of the rate constants for dissociation (koff) and association (kon), Kd = koff/kon. Although the Kd is known by direct measurement, the individual rate constants kon and koff are u...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90290-l
更新日期:1991-08-08 00:00:00
abstract::Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., β-hydroxybutyrate; βOHB) from the liver into the systemic circulation. To da...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2018.12.005
更新日期:2019-02-01 00:00:00
abstract::Bovine serum albumin (BSA) catalyzes the o-rearrangement of the reactive electrophile, N-sulfooxy-2-acetylaminofluorene (NSF), a potential ultimate hepatocarcinogen in the rat, to the nonmutagenic sulfuric acid esters of 1- and 3-hydroxy-2-acetylaminofluorene. Conversion of NSF was proportional to BSA concentrations r...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90678-3
更新日期:1989-11-15 00:00:00
abstract::Diethyl esters of the glutathione S-conjugate S-p-bromobenzylglutathione, an inhibitor of glyoxalase I, and S-p-nitrobenzoxycarbonylglutathione, an inhibitor of glyoxalase II, induced growth arrest and toxicity in human leukaemia 60 cells in culture. The median growth inhibitory concentration IC50 values were 8.3 micr...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90680-h
更新日期:1992-12-15 00:00:00
abstract::Pyridine N-oxide derivatives represent a new class of anti-HIV compounds for which some members exclusively inhibit HIV-1 RT, whereas other members act, additionally or alternatively, at a post-integrational event in the replicative cycle of HIV. A prototype pyridine N-oxide derivative, JPL-32, inhibited tumor necrosi...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2005.12.025
更新日期:2006-04-14 00:00:00
abstract::The reaction mechanism of DNA topoisomerase II (TOP2) involves a covalent double-strand break intermediate in which the enzyme is coupled to DNA via a 5'-phosphotyrosyl bond. This normally transient enzyme-bridged break is stabilised by drugs such as mitoxantrone, mAMSA, etoposide, doxorubicin, epirubicin and idarubic...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2015.12.015
更新日期:2016-03-01 00:00:00
abstract::The neuroprotective effects of adenosine are well-recognized. Recently, propentofylline, a xanthine derivative, has been shown to increase extracellular concentrations of adenosine in ischemic brain and to limit the extent of neuronal damage in experimental models of cerebral ischemia. Since the concentration of adeno...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90499-m
更新日期:1993-09-01 00:00:00
abstract::Tirapazamine (SR 4233) is a bioreductive antitumour drug in Phase III clinical trial which is activated in hypoxic tumour regions to generate a cytotoxic species. Electron paramagnetic resonance (EPR) spectrometry was used to investigate directly the formation of free radicals as the result of tirapazamine reduction b...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(00)00487-1
更新日期:2000-12-15 00:00:00