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Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice.

ABSTRACT: The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression of one arylacetamide deacetylase (Aadac) and 11 carboxylesterases (Cess) by 15 microsomal enzyme inducers (MEIs) was examined in livers of male C57BL/6 mice. The data demonstrated that Aadac mRNA expression was suppressed by three aryl hydrocarbon receptor (AhR) ligands, two constitutive androstane receptor (CAR) activators, two pregnane X receptor (PXR) ligands, and one nuclear factor erythroid 2-related factor 2 (Nrf2) activator. Ces1 subfamily mRNA expression was not altered by most of the MEIs, whereas Ces2 subfamily mRNA was readily induced by the activators of CAR, PXR, and Nrf2 but not by peroxisome proliferator-activated receptor ? activators. Studies using null mice demonstrated that 1) AhR was required for the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated suppression of Aadac and Ces3a; 2) CAR was involved in the 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene-mediated induction of Aadac, Ces2c, Ces2a, and Ces3a; 3) PXR was required for the pregnenolone-16?-carbonitrile-mediated induction of Aadac, Ces2c, and Ces2a; 4) Nrf2 was required for the oltipraz-mediated induction of Ces1g and Ces2c; and 5) PXR was not required for the DEX-mediated suppression of Cess in livers of mice. In conclusion, the present study systematically investigated the regulation of Cess by MEIs in livers of mice and demonstrated that MEIs modulated mRNA expression of mouse hepatic Cess through the activation of AhR, CAR, PXR, and/or Nrf2 transcriptional pathways.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3362786 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice.

Zhang Youcai Y Cheng Xingguo X Aleksunes Lauren L Klaassen Curtis D CD

Drug metabolism and disposition: the biological fate of chemicals 20120319 6

The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression of one arylacetamide deacetylase (Aadac) and 11 carboxylesterases (Cess) by 15 microsomal enzyme inducers (MEIs) was examined in livers of male C57BL/6 mice. The data demonstrated that Aadac mRNA expression was suppressed by three aryl hydrocarbon receptor (AhR) ligands, two constitutive androstane receptor (CAR) activators, two p ...[more]

PMID: 22429928

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Project description:Background & aimsThe ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize the fibroblast growth factor (FGF)-15 produced by mouse intestine. This results in up-regulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool. We investigated whether abnormal bile acid signaling affects the hepatostat in mice.MethodsWe crossed Fah(-/-), Rag2(-/-), Il2r(-/-) mice with nonobese diabetic mice to create FRGN mice, whose livers can be fully repopulated with human hepatocytes. We inserted the gene for human FGF19 (ortholog to mouse Fgf15), including regulatory sequences, into the FRGN mice to create FRGN19(+) mice. Livers of FRGN19(+) mice and their FRGN littermates were fully repopulated with human hepatocytes. Liver tissues were collected and bile acid pool sizes and RNA sequences were analyzed and compared with those of mice without humanized livers (controls).ResultsLivers were larger in FRGN mice with humanized livers (13% of body weight), compared with control FRGN mice; they also had much larger bile acid pools and aberrant bile acid signaling. Livers from FRGN19(+) normalized to 7.8% of body weight, and their bile acid pool and signaling more closely resembled that of control FRGN19(+) mice. RNA sequence analysis showed activation of the Hippo pathway, and immunohistochemical and transcription analyses revealed increased hepatocyte proliferation, but not apoptosis, in the enlarged humanized livers of FRGN mice. Cell sorting experiments showed that although healthy human liver does not produce FGF19, nonparenchymal cells from cholestatic livers produce FGF19.ConclusionsIn mice with humanized livers, expression of an FGF19 transgene corrects bile acid signaling defects, resulting in normalization of bile acid synthesis, the bile acid pool, and liver size. These findings indicate that liver size is, in part, regulated by the size of the bile acid pool that the liver must circulate.

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Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice.

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Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice.

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