Disease relevance of NSC7098

• Toxicity and blood concentrations of xylazine and its metabolite, 2,6-dimethylaniline, in rats after single or continuous oral administrations [1].
• The xylidide 2,6-dimethylaniline (2,6-DMA) has produced carcinomas and papillary adenomas in the nasal cavity of rats at high dietary doses (3000 ppm) in a 2-yr bioassay [2].

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

• Results indicated that, in hepatocytes from both phenobarbital-induced and non-induced mice, the binding of 2,6-DMA was also highly selective with the most prominent target being the 58 kD cytosolic protein [11].
• Oxidation of 2,6-dimethylaniline by recombinant human cytochrome P450s and human liver microsomes [7].
• 2,6-Dimethylaniline (2,6-DMA) is classified as a rodent nasal cavity carcinogen and a possible human carcinogen [7].
• Male ICR mice were administered a single oral dose of 350, 175 or 87.5 mg/kg of 2,6-xylidine by oral gavage and bone marrow was extracted from the femurs 24, 48 and 72 h thereafter [10].
• Thus, the carcinogenic effect of 2,6-xylidine toward the nasal mucosa in rats is correlated with a high capacity of this tissue to bioactivate the compound [12].

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

• Metabolic activation of 2,6-xylidine in the nasal olfactory mucosa and the mucosa of the upper alimentary and respiratory tracts in rats [12].
• The second major alteration was an increase in the relative rate of biosynthesis of a 32-kDa protein (p32) following exposure and recovery from APAP and 3,5-DMA but not 2,6-DMA [16].
• 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 [17].

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].

References