o-Aminoazotoluene does induce the enzymes of its own mutagenic activation in mouse liver

Mikhailova, Olga N.; Vasyunina, E. A.; Ovchinnikova, L.P.; Gulyaeva, L. F.; Timofeeva, O. A.; Филипенко, М. Л.; Каледин, В. И.

doi:10.1016/j.tox.2005.03.006

Cited by 9 publications

(3 citation statements)

References 18 publications

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“…On the other hand, the structural analogue of OAT (the isomeric DAB) 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), which is hepatocarcinogenic to rats, rarely causes tumors in mice (Merkulova et al, 2005). Although the mechanisms of hepatocarcinogenicity of these compounds remain unclear, it is known that they can activate drug metabolism, including both phase I xenobiotic-metabolizing enzymes (CYP450s) and phase II enzymes (such as UGTs and SULTs) and transporters (Mikhailova et al, 2005). Xenobiotic-inducible expression of hepatic biotransformation enzymes and transporters is regulated by the xenobiotic-responsive transcription factors Aryl-hydrocarbon receptor (Ah-R), Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and others (Xu et al, 2005; Stanley et al, 2006; Pascussi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

Сметанина

Pakharukova

Kurinna

et al. 2011

Toxicology and Applied Pharmacology

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2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepatic mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car−/−) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car−/− livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor.

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Section: Introductionmentioning

confidence: 99%

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

Сметанина

Pakharukova

Kurinna

et al. 2011

Toxicology and Applied Pharmacology

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“…These nodules show several morphologic, biochemical, and molecular similarities to neoplastic and dysplastic nodules preceding the development of human HCC (Kohara et al, 2001;Ohsawa et al, 2000;Bailey et al, 1996;Kaledin and Alekseeva, 1978;Kaledin et al, 1978a,b). Previously, we established that mouse susceptibility to OAT-induced liver tumors does not result from different OAT metabolism or OAT genotoxicity in resistant and susceptible mice (Mikhailova et al, 2005;Zacharova et al, 2003;Timofeeva et al, 2000;Kaledin et al, , 1985.…”

Section: Introductionmentioning

confidence: 96%

Effects of o-aminoazotoluene on liver regeneration and p53 activation in mice susceptible and resistant to hepatocarcinogenesis

et al. 2008

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“…Later studies of the mechanism of carcinogenic activity of aminoazostains were carried out mainly on mono-and dimethyl derivatives of aminoazobenzene in rats, while OAT was used in just solitary studies. It exhibited slight hepatotoxic and clastogenic activities [11,12] and rather high mutagenic activity, manifesting in bacterial tests in vitro in the presence of microsomal and cytoplasmic hepatic enzymes [7,8]. The OAT mutagenic metabolites formed under the effects of enzymes from animals sensitive and resistant to its hepatocarcinogenic activity [13].…”

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confidence: 99%

Suppression of Sulfoconjugation Reduces the Protective Effect of Ortho-Aminoazotoluene on Hepatocarcinogenesis Induced by Diethylnitrosamine in Mice

et al. 2014

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The effects of ortho-aminoazotoluene on carcinogenic activity of diethylnitrosamine were studied in CBA and ICR mice. Injection of ortho-aminoazotoluene before and after diethylnitrosamine led to a significant reduction of its anticarcinogenic effect, judging from significantly lower level of liver tumors. Pentachlorophenol, inhibitor of sulfotransferase (catalyzing the terminal stage of ortho-aminoazotoluene metabolic activity), stimulated its carcinogenic effect on mouse liver. On the other hand, pentachlorophenol reduced the protective effect of ortho-aminoazotoluene on diethylnitrosamine-induced hepatocarcinogenesis in mice. Presumably, the carcinogenic and anticarcinogenic effects of ortho-aminoazotoluene were realized by its initial form or intermediate (non-sulfated) metabolites.

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o-Aminoazotoluene does induce the enzymes of its own mutagenic activation in mouse liver

Cited by 9 publications

References 18 publications

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

Effects of o-aminoazotoluene on liver regeneration and p53 activation in mice susceptible and resistant to hepatocarcinogenesis

Suppression of Sulfoconjugation Reduces the Protective Effect of Ortho-Aminoazotoluene on Hepatocarcinogenesis Induced by Diethylnitrosamine in Mice

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