Inhibition of human CYP1A2 oxidation of 5,6-dimethyl-xanthenone-4-acetic acid by acridines: a molecular modelling study.


: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.


Paxton JW,Kestell P,Chiang D,Zhou S,Lewis DF





Has Abstract


2005-08-01 00:00:00














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    abstract::1. Activation of bulbospinal neurons projecting from the C1 area of the rostral ventrolateral medulla evokes a pressor response. The nature of the neurotransmitters involved in mediating this response at spinal cord level has not been established. 2. Amino acid antagonists were introduced into the spinal subarachnoid ...

    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 杂志文章


    authors: Mills EH,Minson JB,Pilowsky PM,Chalmers JP

    更新日期:1988-02-01 00:00:00

  • Both extracellular ATP and shear stress regulate the release of nitric oxide in rat caudal artery.

    abstract::1. To elucidate the physiological role of nitric oxide (NO) in regulating vascular tone, the effects of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, on the vasoconstrictor response to noradrenaline (NA) in rat caudal artery was examined. 2. NG-Nitro-L-arginine methyl ester significantly potenti...

    journal_title:Clinical and experimental pharmacology & physiology

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    authors: Kwon YM,Shinozuka K,Kagota S,Yamaguchi Y,Nakamura K,Kunitomo M

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  • Airway protection following simulated gastro-oesophageal reflux in sedated and sleeping neonatal piglets during active sleep.

    abstract::1. In infants, promethazine has been implicated in the pathogenesis of sleep apnoea, apparent life threatening events (ALTE) and the Sudden Infant Death syndrome (SIDS). The aim of the present study was to investigate, in a neonatal animal, the effects of a commonly used promethazine-containing medication on airway pr...

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    authors: McKelvey GM,Post EJ,Wood AK,Jeffery HE

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    journal_title:Clinical and experimental pharmacology & physiology

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    authors: Omodani H,Kinugawa T,Ogino K,Furuse Y,Yamaguchi M,Mori M,Endo A,Kato M,Kato T,Osaki S,Miyakoda H,Igawa O,Hisatome I,Shigemasa C

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    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 杂志文章,评审


    authors: Head RJ

    更新日期:1989-06-01 00:00:00

  • GABA in the control of sympathetic preganglionic neurons.

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    journal_title:Clinical and experimental pharmacology & physiology

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    authors: Llewellyn-Smith IJ

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  • Reperfusion injury in the human forearm is mild and not attenuated by short-term ischaemic preconditioning.

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    journal_title:Clinical and experimental pharmacology & physiology

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    authors: Kilian JG,Nakhla S,Griffith K,Harmer J,Skilton M,Celermajer DS

    更新日期:2005-01-01 00:00:00

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    authors: Kujal P,Chábová VČ,Vernerová Z,Walkowska A,Kompanowska-Jezierska E,Sadowski J,Vaňourková Z,Husková Z,Opočenský M,Skaroupková P,Schejbalová S,Kramer HJ,Rakušan D,Malý J,Netuka I,Vaněčková I,Kopkan L,Cervenka L

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    abstract::1. The effects of the alpha-beta-adrenergic antagonist labetalol on the activation of human platelets by adrenaline and other aggregating stimuli have been investigated. 2. Labetalol inhibited platelet aggregation and secretion induced by collagen and the second phase of aggregation caused by ADP, platelet activating ...

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    authors: Anfossi G,Trovati M,Lanzio M,Mularoni E,Massucco P,Emanuelli G

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    authors: Lucafò M,Bravin V,Tommasini A,Martelossi S,Rabach I,Ventura A,Decorti G,De Iudicibus S

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    authors: Iwamoto T,Miura T,Urabe K,Itoya M,Shimamoto K,Iimura O

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  • Calmodulin-antagonist drugs and porcine malignant hyperpyrexia.

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    authors: Collins SP,White MD,Denborough MA

    更新日期:1988-06-01 00:00:00

  • The many essential interfaces of clinical pharmacology.

    abstract::1. Clinical pharmacology requires numerous skills and most activities involve interactions with other specialities, both clinical and experimental. 2. A range of experts has had a major influence on the nature and design of my research, which is illustrated by the evolution of my knowledge of adverse drug reactions an...

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    abstract::1. Treatment with angiotensin converting enzyme (ACE) inhibitors ameliorates human and experimental diabetic nephropathy, possibly as a result of changes in angiotensin II (AngII) and/or bradykinin concentrations. However, ACE is an indiscriminate enzyme, which hydrolyses numerous vasoactive peptides at two catalytic ...

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    journal_title:Clinical and experimental pharmacology & physiology

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    authors: Reith D,Medlicott NJ,Kumara De Silva R,Yang L,Hickling J,Zacharias M

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    authors: Silagy CA,McNeil JJ,McGrath BP

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    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 杂志文章


    authors: Hodsman GP,Jackson B,Debrevi LM,Ogawa K,Johnston CI

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    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 杂志文章


    authors: Wang Y,Zhao S,Wu Z,Feng Y,Zhao C,Zhang C

    更新日期:2015-05-01 00:00:00

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    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 临床试验,杂志文章


    authors: Harper RM,Gozal D,Bandler R,Spriggs D,Lee J,Alger J

    更新日期:1998-06-01 00:00:00

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    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 杂志文章


    authors: Shimizu T,Yamamoto M,Zou S,Shimizu S,Higashi Y,Saito M

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    journal_title:Clinical and experimental pharmacology & physiology

    pub_type: 杂志文章


    authors: Kunes J,Jelínek J

    更新日期:1979-09-01 00:00:00