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Chemical Compound Review

Furafilina     3-(2-furylmethyl)-1,8- dimethyl-7H-purine-2...

Synonyms: Furafylline, Furafyllinum, Lopac-F-124, CHEMBL405845, SureCN191214, ...
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Disease relevance of AIDS-108351

  • This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity [1].
  • When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg) [1].

High impact information on AIDS-108351

  • Furafylline inhibited this reaction by > 99% in all subjects, thus demonstrating its applicability to determining the contribution of CYP1A2 to a given reaction in vivo [2].
  • Treatment of individual human liver microsomes (HLM) with TAO resulted in an average 20% inhibition of AFB1-8,9-epoxide formation at 16 microM AFB1, whereas incubation of HLM with furafylline at 16 microM AFB1 resulted in an average 72% inhibition of AFB1-8,9-epoxide formation at 16 microM AFB1 [3].
  • Of a number of cytochrome P450 inhibitors investigated, only furafylline inhibited markedly the conversion of melatonin to 6-sulphatoxymelatonin without any concomitant effect on the sulphoconjugation of 6-hydroxymelatonin [4].
  • Addition of the CYP 450 1A2 inhibitor, furafylline, completely inhibited the formation of 5-OH-PhIP in incubations with human S9 [5].
  • Direct characterization of the selectivity of furafylline as an inhibitor of human cytochromes P450 1A1 and 1A2 [6].

Biological context of AIDS-108351


Anatomical context of AIDS-108351

  • Furafylline inhibited the N-demethylation by about 60% at the low and high substrate concentrations in microsomes from both the EM and PM livers [12].
  • Accordingly, application of a sigmoid Vmax model equivalent to the Hill equation produced excellent fits to the cDNA-expressed CYP3A4 data and also to the data from HLMs pretreated with furafylline to remove CYP1A2 [13].
  • After induction with 1,2-benzanthracene, the CYP1A1 selective inhibitor, alpha-naphthoflavone, and the CYP1A2 selective inhibitor, furafylline, effectively inhibited enzyme activities with IC(50)s of 2.4 microM and 12.8 microM, respectively, in microsomes from both trophoblasts culture systems [14].
  • The aim of this study was to characterize CYP1A in untreated hepatocytes of cynomolgus monkey using two specific CYP1A inhibitors (alpha-naphthoflavone and furafylline) [15].

Associations of AIDS-108351 with other chemical compounds

  • The contribution of CYP1A2 to the metabolism of the dietary heterocyclic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in vivo in humans, has been determined with furafylline, a highly selective inhibitor of this enzyme [2].
  • The CYP1A2 inhibitor furafylline diminished the formation of both HONH-PhIP glucuronide conjugates in a concentration-dependent manner, however, levels of 4'-HO-PhIP were unchanged, indicating that CYP1A2 does not significantly contribute to 4'-hydroxylation of PhIP [16].
  • The rapid loss of human CYP1A2 (cytochrome P450 1A2) activity caused by the 8-methylxanthine furafylline is investigated with the aim of determining whether a stable covalent adduct of the xanthine to the enzyme could be identified [17].
  • Formation of HAMC in human liver microsomes could be completely inhibited by quinidine, at a concentration of 0.5 microM selective for P450 2D6, and furafylline, at a concentration of 30 microM selective for P450 1A2 [18].
  • At 50 microM MPTP, N-demethylase activity in human liver microsomes was also inhibited by furafylline (10 microM) and ketoconazole (2 microM) (mean inhibition 39 and 13%, respectively; n = 11 livers) [19].

Gene context of AIDS-108351


Analytical, diagnostic and therapeutic context of AIDS-108351

  • A group of 6 healthy male volunteers received either placebo or 125 mg furafylline, in a double-blind balanced crossover design, 2 h prior to consuming a test meal of fried beef containing a known amount of amines [2].
  • When furafylline was administered to human volunteers before ingestion of fried beef, we showed that > 90% of MeIQx and approximately 70% of PhIP elimination could be inhibited, demonstrating the extent to which activation occurred in man [25].


  1. Accumulation of caffeine in healthy volunteers treated with furafylline. Tarrus, E., Cami, J., Roberts, D.J., Spickett, R.G., Celdran, E., Segura, J. British journal of clinical pharmacology. (1987) [Pubmed]
  2. CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans. Boobis, A.R., Lynch, A.M., Murray, S., de la Torre, R., Solans, A., Farré, M., Segura, J., Gooderham, N.J., Davies, D.S. Cancer Res. (1994) [Pubmed]
  3. Role of human microsomal and human complementary DNA-expressed cytochromes P4501A2 and P4503A4 in the bioactivation of aflatoxin B1. Gallagher, E.P., Wienkers, L.C., Stapleton, P.L., Kunze, K.L., Eaton, D.L. Cancer Res. (1994) [Pubmed]
  4. Contribution of CYP1A2 in the hepatic metabolism of melatonin: studies with isolated microsomal preparations and liver slices. Skene, D.J., Papagiannidou, E., Hashemi, E., Snelling, J., Lewis, D.F., Fernandez, M., Ioannides, C. J. Pineal Res. (2001) [Pubmed]
  5. N-acetyltransferase-dependent activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine: formation of 2-amino-1-methyl-6-(5-hydroxy)phenylimidazo [4,5-b]pyridine, a possible biomarker for the reactive dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Frandsen, H., Alexander, J. Carcinogenesis (2000) [Pubmed]
  6. Direct characterization of the selectivity of furafylline as an inhibitor of human cytochromes P450 1A1 and 1A2. Tassaneeyakul, W., Birkett, D.J., Veronese, M.E., McManus, M.E., Tukey, R.H., Miners, J.O. Pharmacogenetics (1994) [Pubmed]
  7. Metabolism of the food derived mutagen and carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) by human liver microsomes. Zhao, K., Murray, S., Davies, D.S., Boobis, A.R., Gooderham, N.J. Carcinogenesis (1994) [Pubmed]
  8. Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction. Peterson, T.C., Peterson, M.R., Wornell, P.A., Blanchard, M.G., Gonzalez, F.J. Biochem. Pharmacol. (2004) [Pubmed]
  9. Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes. Bylund, J., Kunz, T., Valmsen, K., Oliw, E.H. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  10. Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. Kunze, K.L., Trager, W.F. Chem. Res. Toxicol. (1993) [Pubmed]
  11. Effect of cigarette smoke on the mutagenic activation of environmental carcinogens by rodent liver. Koide, A., Fuwa, K., Furukawa, F., Hirose, M., Nishikawa, A., Mori, Y. Mutat. Res. (1999) [Pubmed]
  12. Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. Koyama, E., Chiba, K., Tani, M., Ishizaki, T. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  13. The kinetics of aflatoxin B1 oxidation by human cDNA-expressed and human liver microsomal cytochromes P450 1A2 and 3A4. Gallagher, E.P., Kunze, K.L., Stapleton, P.L., Eaton, D.L. Toxicol. Appl. Pharmacol. (1996) [Pubmed]
  14. The presence of inducible cytochrome P450 types 1A1 and 1A2 in the BeWo cell line. Avery, M.L., Meek, C.E., Audus, K.L. Placenta (2003) [Pubmed]
  15. Characterization of CYP1A in hepatocytes of cynomolgus monkeys (Macaca fascicularis) and induction by different substituted polychlorinated biphenyls (PCBs). Van Der Burght, A.S., Kreikamp, A.P., Horbach, G.J., Seinen, W., Van Den Berg, M. Arch. Toxicol. (1998) [Pubmed]
  16. Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rat and human hepatocytes. Langouët, S., Paehler, A., Welti, D.H., Kerriguy, N., Guillouzo, A., Turesky, R.J. Carcinogenesis (2002) [Pubmed]
  17. Mechanism-based inactivation of human cytochrome P450 1A2 by furafylline: detection of a 1:1 adduct to protein and evidence for the formation of a novel imidazomethide intermediate. Racha, J.K., Rettie, A.E., Kunze, K.L. Biochemistry (1998) [Pubmed]
  18. Design, synthesis, and characterization of 7-methoxy-4-(aminomethyl)coumarin as a novel and selective cytochrome P450 2D6 substrate suitable for high-throughput screening. Onderwater, R.C., Venhorst, J., Commandeur, J.N., Vermeulen, N.P. Chem. Res. Toxicol. (1999) [Pubmed]
  19. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2 and 3A4--implications for susceptibility to Parkinson's disease. Coleman, T., Ellis, S.W., Martin, I.J., Lennard, M.S., Tucker, G.T. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  20. Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes. Piver, B., Fer, M., Vitrac, X., Merillon, J.M., Dreano, Y., Berthou, F., Lucas, D. Biochem. Pharmacol. (2004) [Pubmed]
  21. A study of the expression of the xenobiotic-metabolising cytochrome P450 proteins and of testosterone metabolism in bovine liver. Sivapathasundaram, S., Magnisali, P., Coldham, N.G., Howells, L.C., Sauer, M.J., Ioannides, C. Biochem. Pharmacol. (2001) [Pubmed]
  22. Benzo(a)pyrene exposure induces CYP1A1 activity and expression in human endometrial cells. Bao, H., Vepakomma, M., Sarkar, M.A. J. Steroid Biochem. Mol. Biol. (2002) [Pubmed]
  23. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Baldwin, S.J., Clarke, S.E., Chenery, R.J. British journal of clinical pharmacology. (1999) [Pubmed]
  24. Metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin by human hepatic cytochrome P450 isoforms. Renwick, A.B., Surry, D., Price, R.J., Lake, B.G., Evans, D.C. Xenobiotica (2000) [Pubmed]
  25. Assessing human risk to heterocyclic amines. Gooderham, N.J., Murray, S., Lynch, A.M., Yadollahi-Farsani, M., Zhao, K., Rich, K., Boobis, A.R., Davies, D.S. Mutat. Res. (1997) [Pubmed]
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