Abstract:
:1. The aim of the present study was to investigate the structural requirements for the inhibition of 6-methyl-hydroxylation of the antitumour agent 5,6-dimethyl-xanthenone-4-acetic acid (DMXAA) by acridine analogues and use a CYP1A2 homology model to provide some insight into this interaction. 2. Concentrations causing 50% inhibition (IC50) of the 6-methylhydroxylation of DMXAA were determined in human liver microsomes in the presence of various acridines. Some of the acridines were also tested for their ability to inhibit the CYP1A2-mediated 7-ethoxyresorufin O-de-ethylation. The molecular modelling studies of human CYP1A2 used the crystal structure of rabbit CYP2C5 as a template based on protein sequence homology and an interactive docking procedure using a dynamic hydrogen bond feature. 3. The in vitro IC50 studies for the inhibition of 6-methylhydroxylation of DMXAA indicated: (i) the importance of the position of the carboxamide side-chain on the acridine nucleus (and, to a lesser extent, its composition); (ii) the addition of hydroxyl groups to the 5-, 6- and 7-position of the acridine nucleus diminished the inhibitory potency; and (iii) amsacrine (acridine nucleus with methansulphonanilide side-chain at the 9-position) had no significant inhibitory effect. Similar structural trends were observed for the inhibition of O-de-ethylation of 7-ethoxyresorufin by acridines, supporting the involvement of CYP1A2 in DMXAA 6-methyl hydroxylation. 4. The molecular modelling studies indicated: (i) both DMXAA and N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) form two hydrogen bonds plus putative pi-pi stacking interactions with the CYP1A2-binding domain, typical of CYP1A2 substrates and inhibitors; (ii) the DMXAA 6-methyl group is 4.0 A from the central iron atom of the heme moiety and ideal for oxidation; (iii) the known oxidation sites for DACA are orientated away from the heme iron, supporting the non-involvement of CYP1A2; and (iv) amsacrine did not fit the putative CYP1A2 site owing to the steric hindrance of the bulky methanesulphonanilide side-chain. 5. These results suggest that docking studies with this homology model may be useful in the design of further acridine anticancer agents, in particular to identify agents that do not interact either as substrates or inhibitors with the CYP1A2-binding domain.
journal_name
Clin Exp Pharmacol Physioljournal_title
Clinical and experimental pharmacology & physiologyauthors
Paxton JW,Kestell P,Chiang D,Zhou S,Lewis DFdoi
10.1111/j.0305-1870.2005.04243.xkeywords:
subject
Has Abstractpub_date
2005-08-01 00:00:00pages
633-9issue
8eissn
0305-1870issn
1440-1681pii
CEP4243journal_volume
32pub_type
杂志文章abstract::Diets rich in saturated fats and cholesterol contribute to the incidence of hyperlipidaemia. An altered lipid profile is a major factor responsible for the development of CVD. Male Wistar rats were fed with a high-fat diet (HFD) (suspension (w/v) of 0.5% cholesterol, 3% coconut oil and 0.25% cholic acid for 30 days) t...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/1440-1681.13221
更新日期:2020-04-01 00:00:00
abstract::1. The low molecular weight heparin (LMWH) dalteparin is used, for example, to prevent primary venous thromboembolism in patients undergoing surgery or in medically ill patients. The anticoagulant activity of dalteparin can be monitored by measuring anti-factor Xa levels and activated partial thromboplastin time (aPTT...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.2011.05593.x
更新日期:2011-11-01 00:00:00
abstract::Pressor responsiveness to angiotensin II (AII) and phenylephrine (PE) was examined before and after 5 days of ACTH (1 mg, i.m., daily) or hydrocortisone (200 mg, orally, daily) in six normotensive men. Pulse pressure was higher prior to PE than AII infusion, presumably due to feeding. Systolic blood pressure (SBP) was...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1986.tb00362.x
更新日期:1986-04-01 00:00:00
abstract::The transcription factor, nuclear factor-κB (NF-κB) is a key inducer of inducible nitric oxide synthase (iNOS) gene expression. The aim of the present study was to investigate the potential protective effect of l-arginine (Arg; nitric oxide precursor) and aminoguanidine (inducible nitric oxide synthase inhibitor) agai...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/1440-1681.12287
更新日期:2014-10-01 00:00:00
abstract::1. Twelve treated hypertensive patients (ages 58-71 years) who had also been treated for joint disease participated in a randomized double-blind crossover placebo-controlled study to investigate the effects of indomethacin (25 mg three times daily) on blood pressure and biochemical parameters over a 6-week period. 2. ...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1440-1681.1981.tb00763.x
更新日期:1981-09-01 00:00:00
abstract::Nucleocytoplasmic protein shuttling is integral to the transmission of signals between the nucleus and the cytoplasm. The nuclear/cytoplasmic distribution of proteins of interest can be determined via fluorescence microscopy, following labelling of the target protein with fluorophore-conjugated antibodies (immunofluor...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章,评审
doi:10.1111/1440-1681.12969
更新日期:2018-10-01 00:00:00
abstract::1. The aim of the present study was to perform an in vivo estimation of the Michaelis-Menten constants of the major metabolic pathways of paracetamol (APAP). 2. A two-occasion, single-dose cross-over trial was performed using 60 and 90 mg/kg doses of APAP in healthy patients undergoing third molar dental extraction. P...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.2008.05029.x
更新日期:2009-01-01 00:00:00
abstract::1. There has been considerable recent interest in the possibility that increased intake of dietary anti-oxidants may protect against cardiovascular disease. This is partly due to the knowledge that oxidative events in vivo may play a role in the pathogenesis of atherosclerosis. 2. While dietary anti-oxidants, such as ...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章,评审
doi:10.1046/j.1440-1681.2000.03214.x
更新日期:2000-03-01 00:00:00
abstract::1. There was no significant difference between the systolic blood pressure (SBP) of offspring derived from SHRSP mother and WKY father and the SBP of offspring derived from WKY mother and SHRSP father at the developing stage (5-13 weeks of age). 2. The degree of genetic determinations of SBP in stroke-prone spontaneou...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1991.tb01631.x
更新日期:1991-09-01 00:00:00
abstract::1. The serotonin transporter (SERT) is strongly implicated in the pathogenesis of pulmonary arterial hypertension (PAH) in patients and animal models. Inhibitors of SERT have been reported to attenuate or reverse experimental PAH, which makes them potential therapeutic options for the treatment of PAH in humans. Howev...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.2009.05181.x
更新日期:2009-08-01 00:00:00
abstract::Angiogenesis is a process through which new capillaries are formed from pre-existing ones, which contributes significantly to the pathogenesis of numerous diseases, such as cancer and chronic inflammatory disorders. The β-D-mannuronic acid (M2000) is a novel non-steroidal anti-inflammatory drug (NSAID) with immunosupp...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/1440-1681.12907
更新日期:2018-04-01 00:00:00
abstract::1. Animal and human studies indicate that female sex hormones are protective against the development of coronary atherosclerosis. 2. Experiments on vascular smooth muscle cells suggest a direct effect of oestrogen on vascular tissue. Although oestrogen receptors (ER) in vascular tissues and an association between ER s...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章,评审
doi:10.1111/j.1440-1681.1996.tb02775.x
更新日期:1996-06-01 00:00:00
abstract::1. Although it is well established that hypertension is the main risk factor for stroke, the complexity of cerebrovascular problems related to hypertension is not generally appreciated. 2. Hypertension can cause stroke through many mechanisms. A high intraluminal pressure will lead to extensive alteration in endotheli...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章,评审
doi:10.1046/j.1440-1681.1999.03081.x
更新日期:1999-07-01 00:00:00
abstract::1. Chromium picolinate (CrPic) has been recommended as an alternative therapeutic regimen for Type 2 diabetes mellitus (T2DM). However, the molecular mechanism underlying the action of CrPic is poorly understood. 2. Using normal and insulin-resistant 3T3-L1 adipocytes, we examined the effects of CrPic on the gene tran...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.2009.05164.x
更新日期:2009-08-01 00:00:00
abstract::1. Renin mRNA is present in the kidney and, in lower concentrations, in many extrarenal tissues and serves as an index of renin gene activity, as well as potential renin or prorenin synthesis in cell populations within those tissues. Unfortunately the quantity can be very low. 2. A new, highly sensitive technique is d...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1991.tb01463.x
更新日期:1991-05-01 00:00:00
abstract::1. The transplacental transfer of D-xylose was investigated in the present study. 2. Umbilical perfusion of the rat term placenta was used to study materno-foetal (M-F) and foetomaternal (F-M) transfer of this compound. 3. D-Xylose was found to cross the rat term placenta very quickly in the M-F direction, with subseq...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1998.tb02144.x
更新日期:1998-01-01 00:00:00
abstract::1. In order to explore the mechanisms responsible for the hypernoradrenergic innervation of the vasculature in the spontaneously hypertensive rat (SHR) the tissue content of nerve growth factor messenger ribonucleic acid (NGFmRNA) was examined. 2. The concentration of NGFmRNA was markedly elevated in mesenteric veins ...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1992.tb00502.x
更新日期:1992-08-01 00:00:00
abstract::1. The chronotropic and inotropic effects of the anti-anginal agent SG-75 (2-nicotinamidoethyl nitrate) and 1-verapamil were investigated in isolated blood-perfused canine atrial preparations. The compounds were administered via the cannulated sinus node artery. 2. SG-75 induced a selective negative inotropic as oppos...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1980.tb00062.x
更新日期:1980-03-01 00:00:00
abstract::This study investigated the effect of muscarinic M1 and M2 receptor antagonists on the rocuronium-induced train of four (TOF) fade and tetanic fade, respectively. Ex-vivo phrenic nerves and diaphragms were obtained from adult Sprague-Dawley rats and stabilized in Krebs buffer; the nerve-stimulated muscle TOF fade was ...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/1440-1681.12763
更新日期:2017-07-01 00:00:00
abstract::Based on 28 reported patients, constant features of the syndrome of hypertension and hyperkalaemia are hyperkalaemia, hyperchloraemia, normal renal glomerular function and, in all adult patients, hypertension. Inconstant features include short stature, intellectual impairment and muscle weakness. Levels of renin and a...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1986.tb00358.x
更新日期:1986-04-01 00:00:00
abstract::Responses of the toad isolated rectus abdominis muscle to cumulative doses of carbachol were recorded in the absence or presence of varying concentrations of cimetidine or ranitidine. The corresponding cumulative log concentration-response curves for carbachol were then plotted for each antagonist studied. Cimetidine ...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1986.tb00946.x
更新日期:1986-08-01 00:00:00
abstract::Direct evidence is limited for the association between heart rate variability (HRV) indices and ventricular tachyarrhythmias (VTAs). While galectin-3 (Gal-3) is regarded as a causal factor for cardiac remodelling and a biomarker for arrhythmias, its regulation on VTAs and HVR is unknown. Using aged transgenic (TG) mic...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/1440-1681.13275
更新日期:2020-07-01 00:00:00
abstract::1. The differential identification of the angiotensin AT1A and AT1B receptor subtypes is impaired by the existing>96% homology of both receptors. In the present study, we characterized two polyclonal rabbit peptide antibodies, namely alpha-AT1A and alpha-AT1B, that recognize the C-terminal region of mouse AT1A and AT1...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.2005.04288.x
更新日期:2005-11-01 00:00:00
abstract::1. It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5-HT2A receptor antagonist with a weak alpha1-adrenoc...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1046/j.1440-1681.2003.03809.x
更新日期:2003-03-01 00:00:00
abstract::1. Hypoxia arises in solid tumour because of inefficient blood supply. While hypoxic cells are resistant to radiotherapy and probably to many chemotherapeutic drugs they can, in principle, be turned to advantage through the development of hypoxia-activated cytotoxic drugs (bioreductive drugs). 2. Three general approac...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1995.tb01956.x
更新日期:1995-11-01 00:00:00
abstract::1. The actions of lidocaine on cardiac pacemaker rhythms were studied in anaesthetized dogs and in Purkinje fibres from hearts of the same animals. 2. In vivo, lidocaine (1 mg/kg, intravenously) slowed the sino-atrial (SA) node rhythm (-5.0%), and (during vagal stimulation) prolonged ventricular standstill by +25.1% a...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.1991.tb01429.x
更新日期:1991-03-01 00:00:00
abstract:: NADPH oxidases (Nox) are reactive oxygen species (ROS)-generating enzymes that play important physiological roles in host defence and redox signalling. However, Nox activity is upregulated in the vascular wall during atherosclerosis and contributes to plaque formation by promoting oxidative stress and inflammation. ...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/j.1440-1681.2011.05657.x
更新日期:2012-03-01 00:00:00
abstract::1. The clinical observation that hypertension is more common in males and postmenopausal women than in premenopausal women suggests vascular protective effects of female sex hormones, including hormone-mediated inhibition of vascular tone. The purpose of the present study was to investigate whether the Ca2+ mobilizati...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1046/j.1440-1681.1999.03110.x
更新日期:1999-09-01 00:00:00
abstract::Placental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop pre-eclampsia. In this study, pre-emptive treatment with PlGF to prevent pre-eclampsia was evaluated in an in vivo rodent model of experimental pre-eclampsia (EPE) induced by TNF-α and in an in vitro model of huma...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章
doi:10.1111/1440-1681.13169
更新日期:2020-01-01 00:00:00
abstract::1. The present paper reviews the toxic dinoflagellates found in Singapore waters that produce toxins that can accumulate through marine food chains to cause seafood poisonings. 2. Singapore waters contain dinoflagellate species linked to three types of seafood poisoning: paralytic shellfish poisoning, diarrhetic shell...
journal_title:Clinical and experimental pharmacology & physiology
pub_type: 杂志文章,评审
doi:10.1046/j.1440-1681.2002.03724.x
更新日期:2002-09-01 00:00:00