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MeSH Review


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Disease relevance of Dealkylation


High impact information on Dealkylation

  • The oxidative dealkylation of dimethylnitrosamine (DMN), diethylnitrosamine (DEN), and methylethylnitrosamine (MEN) by Sprague-Dawley rat liver microsomes was studied by a colorimetric assay for the simultaneous analysis of formaldehyde and acetaldehyde [5].
  • The reactive cysteine environment, its position within a groove adjacent to the alkyl-binding cavity and mutational analyses characterize DNA-damage recognition and inhibitor specificity, support a structure-based dealkylation mechanism and suggest a molecular basis for destabilization of the alkylated protein [6].
  • The kinetic and chemical mechanisms of the NADPH and O2-supported dealkylation reactions catalyzed by P450 have been investigated and compared with those catalyzed by P450 and peroxidases when the reactions are supported by peroxides [7].
  • The insensitivity of the PBT to induction except at high doses of phenacetin suggests that phenacetin deethylation is not the rate-limiting process modulating exhaled labeled CO2 in healthy subjects, and that the PBT does not generally reflect normal or induced phenacetin dealkylation rates [8].
  • Moreover, the present study directly establishes that during the conversion of cycloartenol to phytosterol one C4 dealkylation occurs before the removal of the 14 alpha-methyl group [9].

Biological context of Dealkylation


Anatomical context of Dealkylation


Associations of Dealkylation with chemical compounds


Gene context of Dealkylation

  • With the exception of the dealkylation in presence of R-PPF only, which can be described by the Michaelis-Menten model, all CYP2D6-induced reactions were found to follow autoactivation kinetics [22].
  • On the other hand, little or no correlation was found between microsomal CYP2A6 and CYP2E1 or between CYP2E1 and NDEA dealkylation [23].
  • In contrast, the monoclonal antibody MAb 1-7-1, raised against 3-methylcholanthrene-inducible rat cytochromes 450, almost abolished CYP1A1-mediated phenacetin O-deethylation, but had no effect on human liver microsomal- or CYP1A2-catalyzed phenacetin dealkylation [24].
  • The dealkylation of ethoxyresorufin, dextromethorphan, and erythromycin were all shown to be specific reactions for CYP1A2, CYP2D6, and CYP3A4 that allowed direct comparison with kinetic data for HLM [25].
  • In a panel of 14 human liver microsomal preparations, the rate of dealkylation showed a highly significant correlation with CYP3A-mediated testosterone 6beta-hydroxylation but not with reactions of seven other CYP isoforms [26].

Analytical, diagnostic and therapeutic context of Dealkylation


  1. Identification of a new class of cytochrome P450 from a Rhodococcus sp. Roberts, G.A., Grogan, G., Greter, A., Flitsch, S.L., Turner, N.J. J. Bacteriol. (2002) [Pubmed]
  2. Degradation of the thiocarbamate herbicide EPTC (S-ethyl dipropylcarbamothioate) and biosafening by Rhodococcus sp. strain NI86/21 involve an inducible cytochrome P-450 system and aldehyde dehydrogenase. Nagy, I., Schoofs, G., Compernolle, F., Proost, P., Vanderleyden, J., de Mot, R. J. Bacteriol. (1995) [Pubmed]
  3. Polycyclic aromatic hydrocarbons cause hepatic porphyria in iron-loaded C57BL/10 mice: comparison of uroporphyrinogen decarboxylase inhibition with induction of alkoxyphenoxazone dealkylations. Francis, J.E., Smith, A.G. Biochem. Biophys. Res. Commun. (1987) [Pubmed]
  4. CYP4B1 activates 4-ipomeanol in rat lung. Verschoyle, R.D., Philpot, R.M., Wolf, C.R., Dinsdale, D. Toxicol. Appl. Pharmacol. (1993) [Pubmed]
  5. Kinetic studies on the hepatic microsomal metabolism of dimethylnitrosamine, diethylnitrosamine, and methylethylnitrosamine in the rat. Chau, I.Y., Dagani, D., Archer, M.C. J. Natl. Cancer Inst. (1978) [Pubmed]
  6. Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. Daniels, D.S., Mol, C.D., Arvai, A.S., Kanugula, S., Pegg, A.E., Tainer, J.A. EMBO J. (2000) [Pubmed]
  7. Mechanisms of cytochrome P450 and peroxidase-catalyzed xenobiotic metabolism. Hollenberg, P.F. FASEB J. (1992) [Pubmed]
  8. Comparison of the phenacetin and aminopyrine breath tests: effect of liver disease, inducers and cobaltous chloride. Schoeller, D.A., Kotake, A.N., Lambert, G.H., Krager, P.S., Baker, A.L. Hepatology (1985) [Pubmed]
  9. Plant sterol biosynthesis. Identification and characterization of two distinct microsomal oxidative enzymatic systems involved in sterol C4-demethylation. Pascal, S., Taton, M., Rahier, A. J. Biol. Chem. (1993) [Pubmed]
  10. Kinetics of the hydroperoxide-dependent dealkylation reactions catalyzed by rabbit liver microsomal cytochrome P-450. Koop, D.R., Hollenberg, P.F. J. Biol. Chem. (1980) [Pubmed]
  11. Structural and functional investigations on the role of zinc in bifunctional rat peptidylglycine alpha-amidating enzyme. Bell, J., Ash, D.E., Snyder, L.M., Kulathila, R., Blackburn, N.J., Merkler, D.J. Biochemistry (1997) [Pubmed]
  12. Identification of the metabolites of roxithromycin in humans. Zhong, D., Li, X., Wang, A., Xu, Y., Wu, S. Drug Metab. Dispos. (2000) [Pubmed]
  13. Catalysis of the dealkylation/debenzylation of phenoxazone ethers by hemoglobin in the absence of peroxides: implications for investigations of embryonic biotransformation. Juchau, M.R., Chapman, D.E., Yang, H.Y., Lee, Q.P., Namkung, M.J., Hinds, T.R. Drug Metab. Dispos. (1996) [Pubmed]
  14. Conserved structural motifs governing the stoichiometric repair of alkylated DNA by O(6)-alkylguanine-DNA alkyltransferase. Daniels, D.S., Tainer, J.A. Mutat. Res. (2000) [Pubmed]
  15. Immunochemical characterization of multiple forms of cytochrome P-450 in rabbit nasal microsomes and evidence for tissue-specific expression of P-450s NMa and NMb. Ding, X.X., Coon, M.J. Mol. Pharmacol. (1990) [Pubmed]
  16. Metabolism of N-alkyl compounds during the biosynthesis of prostaglandins. N-Dealkylation during prostaglandin biosynthesis. Sivarajah, K., Lasker, J.M., Eling, T.E., Abou-Donia, M.B. Mol. Pharmacol. (1982) [Pubmed]
  17. Cryopreservation of rat and dog hepatocytes for studies of xenobiotic metabolism and activation. Powis, G., Santone, K.S., Melder, D.C., Thomas, L., Moore, D.J., Wilke, T.J. Drug Metab. Dispos. (1987) [Pubmed]
  18. Effects of indole-3-carbinol on biotransformation enzymes in the rat: in vivo changes in liver and small intestinal mucosa in comparison with primary hepatocyte cultures. Wortelboer, H.M., van der Linden, E.C., de Kruif, C.A., Noordhoek, J., Blaauboer, B.J., van Bladeren, P.J., Falke, H.E. Food Chem. Toxicol. (1992) [Pubmed]
  19. N-Demethylation reactions catalyzed by chloroperoxidase. Kedderis, G.L., Koop, D.R., Hollenberg, P.F. J. Biol. Chem. (1980) [Pubmed]
  20. Hepatic microsomal dealkylations. Inhibition by a tyrosine-copper (II) complex provided with superoxide dismutase activity. Richter, C., Azzi, A., Weser, U., Wendel, A. J. Biol. Chem. (1977) [Pubmed]
  21. Isolation of 2-fluorocitrate produced by in vivo dealkylation of 29-fluorostigmasterol in an insect. Prestwich, G.D., Yamaoka, R., Phirwa, S., DePalma, A. J. Biol. Chem. (1984) [Pubmed]
  22. Capillary electrophoretic investigation of the enantioselective metabolism of propafenone by human cytochrome P-450 SUPERSOMES: Evidence for atypical kinetics by CYP2D6 and CYP3A4. Afshar, M., Thormann, W. Electrophoresis (2006) [Pubmed]
  23. High variability of nitrosamine metabolism among individuals: role of cytochromes P450 2A6 and 2E1 in the dealkylation of N-nitrosodimethylamine and N-nitrosodiethylamine in mice and humans. Camus, A.M., Geneste, O., Honkakoski, P., Béréziat, J.C., Henderson, C.J., Wolf, C.R., Bartsch, H., Lang, M.A. Mol. Carcinog. (1993) [Pubmed]
  24. Specificity of substrate and inhibitor probes for human cytochromes P450 1A1 and 1A2. Tassaneeyakul, W., Birkett, D.J., Veronese, M.E., McManus, M.E., Tukey, R.H., Quattrochi, L.C., Gelboin, H.V., Miners, J.O. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  25. Rapid characterization of the major drug-metabolizing human hepatic cytochrome P-450 enzymes expressed in Escherichia coli. McGinnity, D.F., Griffin, S.J., Moody, G.C., Voice, M., Hanlon, S., Friedberg, T., Riley, R.J. Drug Metab. Dispos. (1999) [Pubmed]
  26. N-Dealkylation and hydroxylation of ebastine by human liver cytochrome P450. Hashizume, T., Mise, M., Terauchi, Y., O, L., Fujii, T., Miyazaki, H., Inaba, T. Drug Metab. Dispos. (1998) [Pubmed]
  27. Minimal effect of acute experimental hepatitis induced by lipopolysaccharide/D-galactosamine on biotransformation in rats. Omar H el-D, n.u.l.l., Sanders, R.A., Watkins, J.B. Biochem. Pharmacol. (1996) [Pubmed]
  28. pH-dependent geometric isomerization of roxithromycin in simulated gastrointestinal fluids and in rats. Zhang, S., Xing, J., Zhong, D. Journal of pharmaceutical sciences. (2004) [Pubmed]
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