Tags

Type your tag names separated by a space and hit enter

Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some other 7-hydroxy-4-trifluoromethylcoumarin derivatives and 7-benzyloxyquinoline as fluorescent substrates for rat hepatic cytochrome P450 enzymes.

Abstract

1. The aim of this study was to evaluate a number of derivatives of 7-hydroxy-4-trifluoromethylcoumarin (HFC) and 7-benzyloxyquinoline (7BQ) as novel fluorescent substrates for monitoring rat hepatic cytochrome P450 (CYP) enzyme specificity in a 96- well plate format. The HFC derivatives examined comprised 7-benzyloxy-4-trifluoromethylcoumarin (BFC), 2,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BFBFC), 3,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BTBFC), 2-(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (2TFBFC), 3-(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (3TFBFC) and 3-(trifluoromethoxy)-7-benzyloxy-4-trifluoromethylcoumarin (3TFMeOBFC). 2. The CYP specificity of the fluorescent probe substrates was examined using characterized liver microsomes from male Sprague-Dawley rats treated with beta naphthoflavone (BNF), sodium phenobarbitone (NaPB), isoniazid, pregnenolone-16alpha-carbonitrile (PCN), dexamethasone (DEX) and methylclofenapate to induce CYP1A, CYP2B, CYP2E, CYP3A, CYP3A and CYP4A forms, respectively. Studies were also performed with microsomes from baculovirus-infected insect cells containing rat cDNA-expressed CYP1A1, CYP1A2, CYP2B1, CYP3A1 and CYP3A2. 3. BFC metabolism was most markedly induced by BNF and NaPB, whereas BFBFC metabolism was most markedly induced by PCN and DEX and BTBFC was not metabolized by rat liver microsomes. BFC was a high-affinity substrate for cDNA-expressed CYP1A1 and CYP2B1, whereas BFBFC exhibited a high affinity for CYP3A1 and CYP3A2. 4. The metabolism of 2TFBFC and 3TFBFC was induced by NaPB, PCN and DEX. 3TFBFC was a relatively specific substrate for cDNA-expressed CYP2B1, whereas 2TFBFC could be metabolized by CYP2B1, CYP3A1 and CYP3A2. 5. 3TFMeOBFC metabolism was markedly induced by BNF treatment and 3TFMeOBFC was extensively metabolized by cDNA-expressed CYP1A1. 6. The metabolism of 7BQ to 7-hydroxyquinoline was induced by treatment with PCN and DEX. 7BQ was a substrate for cDNA-expressed CYP3A2 and to a lesser extent for CYP3A1. 7. In summary, some of the HFC derivatives studied and 7BQ are useful fluorescent probe substrates for rat CYP enzymes. BFC appears to be a probe for CYP1A and CYP2B, 2TFBFC for CYP2B and CYP3A and 3TFBFC for CYP2B. While 3TFMeOBFC appears to be a relatively specific probe for CYP1A1, both BFBFC and 7BQ are good probes for the induction of CYP3A.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    TNO BIBRA International Ltd, Carshalton, UK.

    , , , , , , ,

    Source

    MeSH

    Animals
    Aryl Hydrocarbon Hydroxylases
    Coumarins
    Cytochrome P-450 CYP2B6
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme System
    Fluorescent Dyes
    Isoenzymes
    Male
    Microsomes, Liver
    Oxidoreductases, N-Demethylating
    Phenobarbital
    Quinolines
    Rats
    Rats, Sprague-Dawley
    Substrate Specificity

    Pub Type(s)

    Evaluation Studies
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    11780761

    Citation

    Renwick, A B., et al. "Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some Other 7-hydroxy-4-trifluoromethylcoumarin Derivatives and 7-benzyloxyquinoline as Fluorescent Substrates for Rat Hepatic Cytochrome P450 Enzymes." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 31, no. 12, 2001, pp. 861-78.
    Renwick AB, Lavignette G, Worboy PD, et al. Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some other 7-hydroxy-4-trifluoromethylcoumarin derivatives and 7-benzyloxyquinoline as fluorescent substrates for rat hepatic cytochrome P450 enzymes. Xenobiotica. 2001;31(12):861-78.
    Renwick, A. B., Lavignette, G., Worboy, P. D., Williams, B., Surry, D., Lewis, D. F., ... Evans, D. C. (2001). Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some other 7-hydroxy-4-trifluoromethylcoumarin derivatives and 7-benzyloxyquinoline as fluorescent substrates for rat hepatic cytochrome P450 enzymes. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 31(12), pp. 861-78.
    Renwick AB, et al. Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some Other 7-hydroxy-4-trifluoromethylcoumarin Derivatives and 7-benzyloxyquinoline as Fluorescent Substrates for Rat Hepatic Cytochrome P450 Enzymes. Xenobiotica. 2001;31(12):861-78. PubMed PMID: 11780761.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Evaluation of 7-benzyloxy-4-trifluoromethylcoumarin, some other 7-hydroxy-4-trifluoromethylcoumarin derivatives and 7-benzyloxyquinoline as fluorescent substrates for rat hepatic cytochrome P450 enzymes. AU - Renwick,A B, AU - Lavignette,G, AU - Worboy,P D, AU - Williams,B, AU - Surry,D, AU - Lewis,D F, AU - Price,R J, AU - Lake,B G, AU - Evans,D C, PY - 2002/1/10/pubmed PY - 2002/6/22/medline PY - 2002/1/10/entrez SP - 861 EP - 78 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 31 IS - 12 N2 - 1. The aim of this study was to evaluate a number of derivatives of 7-hydroxy-4-trifluoromethylcoumarin (HFC) and 7-benzyloxyquinoline (7BQ) as novel fluorescent substrates for monitoring rat hepatic cytochrome P450 (CYP) enzyme specificity in a 96- well plate format. The HFC derivatives examined comprised 7-benzyloxy-4-trifluoromethylcoumarin (BFC), 2,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BFBFC), 3,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BTBFC), 2-(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (2TFBFC), 3-(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (3TFBFC) and 3-(trifluoromethoxy)-7-benzyloxy-4-trifluoromethylcoumarin (3TFMeOBFC). 2. The CYP specificity of the fluorescent probe substrates was examined using characterized liver microsomes from male Sprague-Dawley rats treated with beta naphthoflavone (BNF), sodium phenobarbitone (NaPB), isoniazid, pregnenolone-16alpha-carbonitrile (PCN), dexamethasone (DEX) and methylclofenapate to induce CYP1A, CYP2B, CYP2E, CYP3A, CYP3A and CYP4A forms, respectively. Studies were also performed with microsomes from baculovirus-infected insect cells containing rat cDNA-expressed CYP1A1, CYP1A2, CYP2B1, CYP3A1 and CYP3A2. 3. BFC metabolism was most markedly induced by BNF and NaPB, whereas BFBFC metabolism was most markedly induced by PCN and DEX and BTBFC was not metabolized by rat liver microsomes. BFC was a high-affinity substrate for cDNA-expressed CYP1A1 and CYP2B1, whereas BFBFC exhibited a high affinity for CYP3A1 and CYP3A2. 4. The metabolism of 2TFBFC and 3TFBFC was induced by NaPB, PCN and DEX. 3TFBFC was a relatively specific substrate for cDNA-expressed CYP2B1, whereas 2TFBFC could be metabolized by CYP2B1, CYP3A1 and CYP3A2. 5. 3TFMeOBFC metabolism was markedly induced by BNF treatment and 3TFMeOBFC was extensively metabolized by cDNA-expressed CYP1A1. 6. The metabolism of 7BQ to 7-hydroxyquinoline was induced by treatment with PCN and DEX. 7BQ was a substrate for cDNA-expressed CYP3A2 and to a lesser extent for CYP3A1. 7. In summary, some of the HFC derivatives studied and 7BQ are useful fluorescent probe substrates for rat CYP enzymes. BFC appears to be a probe for CYP1A and CYP2B, 2TFBFC for CYP2B and CYP3A and 3TFBFC for CYP2B. While 3TFMeOBFC appears to be a relatively specific probe for CYP1A1, both BFBFC and 7BQ are good probes for the induction of CYP3A. SN - 0049-8254 UR - https://www.unboundmedicine.com/medline/citation/11780761/Evaluation_of_7_benzyloxy_4_trifluoromethylcoumarin_some_other_7_hydroxy_4_trifluoromethylcoumarin_derivatives_and_7_benzyloxyquinoline_as_fluorescent_substrates_for_rat_hepatic_cytochrome_P450_enzymes_ L2 - http://www.tandfonline.com/doi/full/10.1080/00498250110074063 DB - PRIME DP - Unbound Medicine ER -