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

Journal Article · Mon Aug 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.05.019· OSTI ID:21587813

Pakharukova, Mariya Y ^[1]; Kurinna, Svitlana M ^[2]; Dong, Bingning; Hernandez, Juan P; Moore, David D ^[3]; Merkulova, Tatyana I ^[1]

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1. Laboratory of Gene Expression Control, Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, prospekt Lavrentyeva 10, Novosibirsk 630090 (Russian Federation)
2. Department of Biochemistry and Molecular Biology, Unit 1000, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (United States)
3. Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030 (United States)

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{sup -/-}) 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{sup -/-} 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. - Highlights: > The azo dye and mouse carcinogen OAT is a very effective mCAR activator. > OAT increases mCAR transactivation in a dose-dependent manner. > OAT CAR-dependently increases the expression of a specific subset of CAR target genes. > OAT induces an unexpectedly deferred, but CAR-dependent hepatocyte proliferation.

• OSTI ID: 21587813
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 1; Other Information: DOI: 10.1016/j.taap.2011.05.019; PII: S0041-008X(11)00210-9; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AZO DYES
BENZENE
BUDR
CARCINOGENS
CYTOCHROMES
DOSES
GENES
LIVER
MESSENGER-RNA
MICE
NEOPLASMS
POLYMERASE CHAIN REACTION
PROLIFERATION
RECEPTORS
ANIMALS
ANTIMETABOLITES
AROMATICS
AZINES
AZO COMPOUNDS
BODY
BROMOURACILS
DIGESTIVE SYSTEM
DISEASES
DRUGS
DYES
GENE AMPLIFICATION
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
HYDROXY COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC BROMINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PIGMENTS
PROTEINS
PYRIMIDINES
RIBOSIDES
RNA
RODENTS
URACILS
VERTEBRATES