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Chemical Compound Review

Bufuralol     1-(7-ethylbenzofuran-2-yl)-2- (tert...

Synonyms: Bufuralolum, dl-Bufuralol, SureCN78552, AGN-PC-005TW6, CHEMBL296035, ...
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Disease relevance of Bufuralol

  • Hydroxylation of the low-extraction drug bufuralol resulted in the formation of 251 +/- 25 nmol 1'OH-bufuralol/gm wet wt/hr in mildly diseased liver tissue and was significantly (p less than 0.01) reduced in liver tissue exhibiting chronic active hepatitis (166 +/- 23 nmol/gm wet wt/hr) and cirrhosis (124 +/- 21 nmol/gm wet wt/hr) [1].
  • Purified recombinant P450 1A2 (expressed in E. coli) produced 1'-, 4-, and 6-hydroxybufuralol in a reconstituted system, although P450 2D6 (expressed in human lymphoblast cell lines) was found to catalyze only bufuralol 1'-hydroxylation.(ABSTRACT TRUNCATED AT 400 WORDS)[2]
  • A rat liver cDNA library was prepared using the expression vector bacteriophage lambda gt11 and plaques were screened using polyclonal antibodies raised to purified rat liver cytochrome P-450UT-H, the major enzyme involved in debrisoquine 4-hydroxylation, bufuralol 1'-hydroxylation, and sparteine delta 5-oxidation [3].
  • All three beta-adrenoceptor antagonists reduced exercise tachycardia, but at the doses chosen the effects of bufuralol were less than those of propranolol [4].
  • Simultaneous hemodynamic and equilibrium radionuclide function measurements were performed at rest and during exercise before and 75 min after oral administration of 30 mg bufuralol, a nonselective beta-adrenoceptor blocking drug, in 10 patients with stable angina pectoris [5].

High impact information on Bufuralol

  • We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes [6].
  • Using two assay systems with different selectivity for the two cytochrome P-450 isozymes catalyzing bufuralol metabolism in human liver, we show that anti-LKM1 exclusively recognizes cytochrome P-450db1 [6].
  • Cigarette smoke condensate strongly inhibited the activation of several potent procarcinogens by human liver microsomes, particularly the reactions catalyzed by P-450 1A2, but was not so inhibitory of the activation reactions catalyzed by P-450 3A4 and of P-450 2D6-catalyzed bufuralol 1'-hydroxylation [7].
  • The only agent to inhibit bufuralol hydroxylation was vinblastine, which did so with a Ki of 90 microM (Km of the enzyme for the substrate = 12 microM) [8].
  • A cDNA coding for an allelic variant of rat IID1, designated IID1v, was isolated that produced a P-450 having a 10-fold lower catalytic activity toward the substrate bufuralol when expressed in COS-1 cells (Matsunaga, E., Zanger, U. M., Hardwick, J. P., Gelboin, H. V., Meyer, U. A., and Gonzalez, F. J. (1989) Biochemistry, 28, 7349-7355) [9].

Chemical compound and disease context of Bufuralol

  • Of greater significance however, was the finding that intact E. coli cells, even in the absence of exogenous NADPH, were able to metabolize bufuralol at rates almost as high as those measured in membranes (4.6 +/- 0.4 min-1 versus 5.7 +/- 0.2 min-1 at 50 microM substrate) [10].
  • CYP2D6, Cyp2d-9 and both mutant CYP2D6 proteins were co-expressed with NADPH cytochrome P-450 reductase as a functional mono-oxygenase system in Escherichia coli and their relative catalytic activities towards bufuralol and testosterone were determined [11].

Biological context of Bufuralol

  • Twenty-four genetic polymorphisms in the CYP2D6 gene were analysed in liver DNA samples of 39 Japanese and 44 Caucasians and compared with CYP2D6 protein levels and bufuralol 1'- and 6-hydroxylation activities in liver microsomes of these human samples [12].
  • The kinetics of bufuralol 1'-hydroxylase activity of hepatic microsomal fractions have been determined in female DA and Fischer 344 rats, strains between which there is a large difference in debrisoquine 4-hydroxylase activity [13].
  • This may mean that the competing drug also is metabolized by P-450dbl and that its metabolism is subject to the same genetic variation as the oxidation of bufuralol [14].
  • Quinidine was a potent inhibitor of the 4-hydroxylation of debrisoquine and the 1'-hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 microM, being around 100 times more potent in this respect than quinine [15].
  • Finally, a similar prediction using literature bufuralol data, coupled with the observed protein binding data, was used to illustrate that the most accurate predictions of bufuralol clearance are obtained when the amount of protein in the incubation is kept to a minimum and the overall incubation time is less than 20 min [16].

Anatomical context of Bufuralol


Associations of Bufuralol with other chemical compounds


Gene context of Bufuralol


Analytical, diagnostic and therapeutic context of Bufuralol


  1. Quantitation of intrinsic drug-metabolizing capacity in human liver biopsy specimens: support for the intact-hepatocyte theory. Meyer, B., Luo, H.S., Bargetzi, M., Renner, E.L., Stalder, G.A. Hepatology (1991) [Pubmed]
  2. Bufuralol hydroxylation by cytochrome P450 2D6 and 1A2 enzymes in human liver microsomes. Yamazaki, H., Guo, Z., Persmark, M., Mimura, M., Inoue, K., Guengerich, F.P., Shimada, T. Mol. Pharmacol. (1994) [Pubmed]
  3. Characterization of a rat liver cytochrome P-450UT-H cDNA clone and comparison of mRNA levels with catalytic activity. Churchill, P.F., Churchill, S.A., Martin, M.V., Guengerich, F.P. Mol. Pharmacol. (1987) [Pubmed]
  4. Peripheral vascular effects of bufuralol in hypertensive and normal subjects: a comparison with propranolol and pindolol. Johnston, G.D., Finch, M.B., Shanks, R.G. Eur. J. Clin. Pharmacol. (1986) [Pubmed]
  5. Acute hemodynamic effects of bufuralol: a beta-adrenoceptor blocking drug with vasodilatory effects. Pfisterer, M., Burckhardt, D., Bühler, F.R., Burkart, F. J. Cardiovasc. Pharmacol. (1984) [Pubmed]
  6. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II. Zanger, U.M., Hauri, H.P., Loeper, J., Homberg, J.C., Meyer, U.A. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  7. Activation of amino-alpha-carboline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and a copper phthalocyanine cellulose extract of cigarette smoke condensate by cytochrome P-450 enzymes in rat and human liver microsomes. Shimada, T., Guengerich, F.P. Cancer Res. (1991) [Pubmed]
  8. Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Relling, M.V., Evans, W.E., Fonné-Pfister, R., Meyer, U.A. Cancer Res. (1989) [Pubmed]
  9. Sequence requirements for cytochrome P-450IID1 catalytic activity. A single amino acid change (Ile380 Phe) specifically decreases Vmax of the enzyme for bufuralol but not debrisoquine hydroxylation. Matsunaga, E., Zeugin, T., Zanger, U.M., Aoyama, T., Meyer, U.A., Gonzalez, F.J. J. Biol. Chem. (1990) [Pubmed]
  10. Functional co-expression of CYP2D6 and human NADPH-cytochrome P450 reductase in Escherichia coli. Pritchard, M.P., Glancey, M.J., Blake, J.A., Gilham, D.E., Burchell, B., Wolf, C.R., Friedberg, T. Pharmacogenetics (1998) [Pubmed]
  11. Determinants of the substrate specificity of human cytochrome P-450 CYP2D6: design and construction of a mutant with testosterone hydroxylase activity. Smith, G., Modi, S., Pillai, I., Lian, L.Y., Sutcliffe, M.J., Pritchard, M.P., Friedberg, T., Roberts, G.C., Wolf, C.R. Biochem. J. (1998) [Pubmed]
  12. Characterization of (+/-)-bufuralol hydroxylation activities in liver microsomes of Japanese and Caucasian subjects genotyped for CYP2D6. Shimada, T., Tsumura, F., Yamazaki, H., Guengerich, F.P., Inoue, K. Pharmacogenetics (2001) [Pubmed]
  13. Bufuralol 1'-hydroxylase activity of the rat. Strain differences and the effects of inhibitors. Boobis, A.R., Seddon, C.E., Davies, D.S. Biochem. Pharmacol. (1986) [Pubmed]
  14. Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism. Fonne-Pfister, R., Meyer, U.A. Biochem. Pharmacol. (1988) [Pubmed]
  15. Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine. Speirs, C.J., Murray, S., Boobis, A.R., Seddon, C.E., Davies, D.S. British journal of clinical pharmacology. (1986) [Pubmed]
  16. Impact of incubation conditions on bufuralol human clearance predictions: enzyme lability and nonspecific binding. Foti, R.S., Fisher, M.B. Drug Metab. Dispos. (2004) [Pubmed]
  17. Debrisoquine/sparteine-type polymorphism of drug oxidation. Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. Gut, J., Catin, T., Dayer, P., Kronbach, T., Zanger, U., Meyer, U.A. J. Biol. Chem. (1986) [Pubmed]
  18. A monoclonal antibody inhibitory to human P450 2D6: a paradigm for use in combinatorial determination of individual P450 role in specific drug tissue metabolism. Gelboin, H.V., Krausz, K.W., Shou, M., Gonzalez, F.J., Yang, T.J. Pharmacogenetics (1997) [Pubmed]
  19. Debrisoquine 4-monooxygenase and bufuralol 1'-monooxygenase activities in bovine and rabbit tissues. Matsuo, Y., Iwahashi, K., Ichikawa, Y. Biochem. Pharmacol. (1992) [Pubmed]
  20. Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey. Sharer, J.E., Shipley, L.A., Vandenbranden, M.R., Binkley, S.N., Wrighton, S.A. Drug Metab. Dispos. (1995) [Pubmed]
  21. Relationship between oxidative metabolism of 2-acetylaminofluorene, debrisoquine, bufuralol, and aldrin in human liver microsomes. McManus, M.E., Boobis, A.R., Minchin, R.F., Schwartz, D.M., Murray, S., Davies, D.S., Thorgeirsson, S.S. Cancer Res. (1984) [Pubmed]
  22. Oxidation of quinidine by human liver cytochrome P-450. Guengerich, F.P., Müller-Enoch, D., Blair, I.A. Mol. Pharmacol. (1986) [Pubmed]
  23. Integrated acquisition of analytical and biopharmaceutical screening data for beta-adrenergic-drugs employing diversified macrocycle supported potentiometric detection in HPLC systems. Bazylak, G., Nagels, L.J. Current medicinal chemistry. (2002) [Pubmed]
  24. A tobacco smoke-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is activated by multiple human cytochrome P450s including the polymorphic human cytochrome P4502D6. Crespi, C.L., Penman, B.W., Gelboin, H.V., Gonzalez, F.J. Carcinogenesis (1991) [Pubmed]
  25. Reconstitution of recombinant cytochrome P450 2C10(2C9) and comparison with cytochrome P450 3A4 and other forms: effects of cytochrome P450-P450 and cytochrome P450-b5 interactions. Yamazaki, H., Gillam, E.M., Dong, M.S., Johnson, W.W., Guengerich, F.P., Shimada, T. Arch. Biochem. Biophys. (1997) [Pubmed]
  26. Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Ma, B., Prueksaritanont, T., Lin, J.H. Drug Metab. Dispos. (2000) [Pubmed]
  27. In vitro evaluation of the disposition of A novel cysteine protease inhibitor. Jacobsen, W., Christians, U., Benet, L.Z. Drug Metab. Dispos. (2000) [Pubmed]
  28. Development of a human lymphoblastoid cell line constitutively expressing human CYP1B1 cDNA: substrate specificity with model substrates and promutagens. Crespi, C.L., Penman, B.W., Steimel, D.T., Smith, T., Yang, C.S., Sutter, T.R. Mutagenesis (1997) [Pubmed]
  29. The CYP2D gene subfamily: analysis of the molecular basis of the debrisoquine 4-hydroxylase deficiency in DA rats. Matsunaga, E., Zanger, U.M., Hardwick, J.P., Gelboin, H.V., Meyer, U.A., Gonzalez, F.J. Biochemistry (1989) [Pubmed]
  30. Determination of bufuralol and its major metabolites in plasma by high-performance liquid chromatography. Haefelfinger, P. J. Chromatogr. (1980) [Pubmed]
  31. Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy. Bonifacio, A., Keizers, P.H., Commandeur, J.N., Vermeulen, N.P., Robert, B., Gooijer, C., van der Zwan, G. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  32. Effect of oxidative polymorphism (debrisoquine/sparteine type) on hepatic first-pass metabolism of bufuralol. Dayer, P., Balant, L., Kupfer, A., Striberni, R., Leemann, T. Eur. J. Clin. Pharmacol. (1985) [Pubmed]
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