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Chemical Compound Review

Xylylamine     2,6-dimethylaniline

Synonyms: o-Xylidine, vic-m-xylidine, TPC-I105, LS-79, PubChem17593, ...
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Disease relevance of NSC7098


High impact information on NSC7098

  • Recent data from the National Toxicology Program reported that a principal metabolite in man, 2,6-dimethylaniline, is carcinogenic in rats [3].
  • 2,6-Xylidine was acylated with haloacyl halides and converted to the target compounds by direct amination or by the Gabriel procedure [4].
  • Experimental evidence for carcinogenicity of monocylic aromatic amines is limited mostly to other organs, but a recent epidemiologic study of bladder cancer found that 2,6-dimethyl- (2,6-DMA), 3,5-dimethyl- (3,5-DMA), and 3-ethylaniline (3-EA) may play a significant role in the etiology of this disease in man [5].
  • The amination was found to proceed with both electron-rich and electron-deficient aryl chlorides and anilines and also utilizes sterically hindered anilines such as 2,6-dimethylaniline and 2-tert-butylaniline [6].
  • In the present study, 2,6-DMA oxidation in vitro by human liver microsomes and recombinant human P450 enzymes was investigated to assess whether the hemoglobin adduct variability could be attributed to metabolic differences [7].

Biological context of NSC7098

  • As with other aromatic amines, 2,6-DMA can undergo metabolic activation through cytochrome p450-mediated N-hydroxylation, followed by O-esterification to a reactive derivative capable of forming DNA adducts [8].
  • This study was undertaken to understand the pharmacokinetics and metabolism of D2624 in rats and humans, with emphasis on the possible formation of 2,6-dimethylaniline (2,6-DMA) [9].
  • Based on plasma AUC analysis, D3017 and 2,6-DMA accounted for > 90% of the dose of D2624 [9].
  • After oral administration of stable isotope-labeled parent drug to rats and GC/MS analysis of plasma samples, two metabolites were identified: D3017, which is the primary alcohol, and 2,6-DMA, formed by amide bond hydrolysis of either D2624 or D3017 [9].
  • The ability of 2,6-xylidine to produce chromosome breakage and/or spindle malformation in vivo was evaluated by an assessment of the capacity of the compound to induce micronuclei in bone marrow polychromatic erythrocytes [10].

Anatomical context of NSC7098


Associations of NSC7098 with other chemical compounds

  • Exposure of the hepatocytes to 10 mM 3,5-dimethyl-acetaminophen (3,5-DMA) or 2,6-dimethyl-acetaminophen (2,6-DMA) permitted dissociation of the oxidative and arylative properties of APAP [13].
  • To evaluate the mechanistic importance of covalent binding in acetaminophen (APAP)-induced hepatotoxicity, we compared the effects of 2,6-dimethylacetaminophen (2,6-DMA) to those of APAP in primary cultures of mouse hepatocytes [11].
  • Benzidine produced a significant (p less than 0.001) dose related increase in the incidence of micronucleated polychromatic erythrocytes (MPE), while 2,6-xylidine had no effect on the frequency of micronucleated cells [14].
  • The formation of D3017 was NADPH-dependent, whereas 2,6-DMA formation was NADPH-independent and probably was catalyzed by amidase(s) enzymes [9].
  • Our results demonstrate that 2,6-DMA, formed by the metabolism of lidocaine, is transferable to bovine and human milk [15].

Gene context of NSC7098


Analytical, diagnostic and therapeutic context of NSC7098

  • Since our affinity-purified anti-APAP antibody did not cross-react with 2,6-DMA, a new antibody specific for 2,6-DMA was prepared and, after affinity purification, was used to detect 2,6-DMA protein adducts by Western blotting [11].
  • In a single-dose (25-225 mg) human volunteer study, the parent drug (D2624) was not detected in plasma at any dose, whereas 2,6-DMA was detected only at the two highest doses (150 and 225 mg) [9].
  • Whole-body autoradiography with freeze-dried or solvent-extracted tissue sections as well as microautoradiography, which were used to trace tissues in the rats accumulating 2,6-xylidine metabolites, showed presence of tissue-bound 2,6-xylidine metabolites in the nasal olfactory mucosa and the mucosa of the upper alimentary and respiratory tracts [12].
  • Taking the above into account, a sensitive and specific amperometric method has been developed, which enables, after separation with the use of HPLC, an accurate determination of the content of 2,6-DMA and o-TLD in various pharmaceutical preparations [18].


  1. Toxicity and blood concentrations of xylazine and its metabolite, 2,6-dimethylaniline, in rats after single or continuous oral administrations. Yasuhara, K., Kobayashi, H., Shimamura, Y., Koujitani, T., Onodera, H., Takagi, H., Hirose, M., Mitsumori, K. The Journal of toxicological sciences. (2000) [Pubmed]
  2. Covalent binding of [14C]-2,6-dimethylaniline to DNA of rat liver and ethmoid turbinate. Short, C.R., Joseph, M., Hardy, M.L. Journal of toxicology and environmental health. (1989) [Pubmed]
  3. 2,6-Dimethylaniline--hemoglobin adducts from lidocaine in humans. Bryant, M.S., Simmons, H.F., Harrell, R.E., Hinson, J.A. Carcinogenesis (1994) [Pubmed]
  4. New antiarrhythmic agents. 6. Quantitative structure-activity relationships of aminoxylidides. Tenthorey, P.A., Block, A.J., Ronfeld, R.A., McMaster, P.D., Byrnes, E.W. J. Med. Chem. (1981) [Pubmed]
  5. DNA adduct formation by 2,6-dimethyl-, 3,5-dimethyl-, and 3-ethylaniline in vivo in mice. Skipper, P.L., Trudel, L.J., Kensler, T.W., Groopman, J.D., Egner, P.A., Liberman, R.G., Wogan, G.N., Tannenbaum, S.R. Chem. Res. Toxicol. (2006) [Pubmed]
  6. Regioselective copper-catalyzed amination of chlorobenzoic acids: synthesis and solid-state structures of N-aryl anthranilic acid derivatives. Mei, X., August, A.T., Wolf, C. J. Org. Chem. (2006) [Pubmed]
  7. Oxidation of 2,6-dimethylaniline by recombinant human cytochrome P450s and human liver microsomes. Gan, J., Skipper, P.L., Tannenbaum, S.R. Chem. Res. Toxicol. (2001) [Pubmed]
  8. The effect of deuterium and fluorine substitution upon the mutagenicity of N-hydroxy-2,6-dimethylaniline. Matilde Marques, M., Gamboa da Costa, G., Blankenship, L.R., Culp, S.J., Beland, F.A. Mutat. Res. (2002) [Pubmed]
  9. Pharmacokinetics and metabolism of the novel anticonvulsant agent N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in rats and humans. Martin, S.W., Bishop, F.E., Kerr, B.M., Moor, M., Moore, M., Sheffels, P., Rashed, M., Slatter, J.G., Berthon-Cédille, L., Lepage, F., Descombe, J.J., Picard, M., Baillie, T.A., Levy, R.H. Drug Metab. Dispos. (1997) [Pubmed]
  10. The in vivo effect of 2,6-xylidine on induction of micronuclei in mouse bone marrow cells. Parton, J.W., Probst, G.S., Garriott, M.L. Mutat. Res. (1988) [Pubmed]
  11. Selective protein arylation by acetaminophen and 2,6-dimethylacetaminophen in cultured hepatocytes from phenobarbital-induced and uninduced mice. Relationship to cytotoxicity. Birge, R.B., Bartolone, J.B., McCann, D.J., Mangold, J.B., Cohen, S.D., Khairallah, E.A. Biochem. Pharmacol. (1989) [Pubmed]
  12. Metabolic activation of 2,6-xylidine in the nasal olfactory mucosa and the mucosa of the upper alimentary and respiratory tracts in rats. Tydén, E., Tjälve, H., Larsson, P. Toxicol. Sci. (2004) [Pubmed]
  13. Dissociation of covalent binding from the oxidative effects of acetaminophen. Studies using dimethylated acetaminophen derivatives. Birge, R.B., Bartolone, J.B., Nishanian, E.V., Bruno, M.K., Mangold, J.B., Cohen, S.D., Khairallah, E.A. Biochem. Pharmacol. (1988) [Pubmed]
  14. The evaluation of a multiple dosing protocol for the mouse bone-marrow micronucleus assay using benzidine and 2,6-xylidine. Parton, J.W., Beyers, J.E., Garriott, M.L., Tamura, R.N. Mutat. Res. (1990) [Pubmed]
  15. Analysis of the lidocaine metabolite 2,6-dimethylaniline in bovine and human milk. Puente, N.W., Josephy, P.D. Journal of analytical toxicology. (2001) [Pubmed]
  16. Selective alterations in the patterns of newly synthesized proteins by acetaminophen and its dimethylated analogues in primary cultures of mouse hepatocytes. Bruno, M.K., Cohen, S.D., Khairallah, E.A. Toxicol. Appl. Pharmacol. (1992) [Pubmed]
  17. Lack of DNA binding in the rat nasal mucosa and other tissues of the nasal toxicants roflumilast, a phosphodiesterase 4 inhibitor, and a metabolite, 4-amino-3,5-dichloropyridine, in contrast to the nasal carcinogen 2,6-dimethylaniline. Jeffrey, A.M., Luo, F.Q., Amin, S., Krzeminski, J., Zech, K., Williams, G.M. Drug and chemical toxicology. (2002) [Pubmed]
  18. Determination of 2,6-dimethylaniline and o-toluidine impurities in preparations for local anaesthesia by the HPLC method with amperometric detection. Baczyński, E., Piwońska, A., Fijałek, Z. Acta poloniae pharmaceutica. (2002) [Pubmed]
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