Pretranslational induction of cytochrome P4501A enzymes by β-naphthoflavone and 3-methylcholanthrene occurs in different liver zones

Oinonen, Teija; Saarikoski, Sirkku T.; Husgafvel‐Pursiainen, Kirsti; Hirvonen, Ari; Ko, Lindros

doi:10.1016/0006-2952(94)00385-8

Cited by 35 publications

(18 citation statements)

References 23 publications

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“…These differences are similar in extent to those seen in extensive zonation studies on the induction of enzymes by various xenobiotics in isolated rat cells (Oinonen et al, 1994).…”

Section: Section 42 Zonal Distribution Of Dna Synthesis In Liversupporting

confidence: 67%

Mechanism of action of liver growth induced by peroxisome proliferators

Amer

2010

Toxicology

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Humans are ubiquitously exposed to peroxisome proliferators including hypolipidemic agents, industrial solvents and natural products. Because of this and the fact that peroxisome proliferators cause non-genotoxic hepatocarcinogenesis in rodents, it is of importance to elucidate the mechanism of action of the peroxisome proliferators in order to provide an assessment of the hazard, if any, of these compounds to humans. It is also known that the peroxisome proliferators begin their actions by inducing hepatic DNA synthesis. Thus, the aim of this thesis was to find genes that could be responsible for triggering the induction of hepatic DNA synthesis caused by peroxisome proliferators, specifically ciprofibrate.First, it was important to indicate when the induction of hepatic DNA synthesis actually happens. This was done with BrdU immunohistochemical procedures. The induction of hepatic DNA synthesis with ciprofibrate in mice was observable only after 4 days making it difficult to specify when the induction actually happened. In rats the induction of hepatic DNA synthesis was found to peak at 24 hours and this system gave the better opportunity to find the genes responsible. The difference in the timing of induced hepatic DNA synthesis between mice and rats implied that there could be a species difference in the mechanism of each species' response to PPAR. With immunohistochemistry it was noticed that there was a difference in the lobular localization of hepatic DNA synthesis in the liver tissues of rats and mice dosed with different inducers, with the rat livers exhibiting periportal distribution while hepatic DNA synthesis in the mice seemed to be distributed throughout the liver tissue.The effects of ciprofibrate or cyproterone acetate on liver gene expression in rats were studied, using cDNA microarrays, transcriptome sequencing and quantitative real-time PCR. A 1-5 hour treatment period was chosen to detect the immediate early gene response, while a 24 hour time point was chosen to elucidate the confounding effects from the hepatic DNA synthesis seen Abeer Amer Page 2 during the 24 hour stimulation. The results showed that ciprofibrate altered the expression of numerous genes including previously known PPARa agonist-responsive genes involved in processes such as PPAR signalling pathways, fatty acid metabolic pathway, cell cycle, palmitoylCoA hydrolase activity, lipid metabolism, inflammatory responses, and stress responses, in addition to a large number of novel candidate genes.Three novel induced genes G0s2, Ccnd1 and Scd1, (and two marker genes CYP4A1 and CYP3A1) were confirmed with quantitative real-time PCR. The G0s2, Ccnd1 and Scd1 were found to be up-regulated at the hours 1 and 3 after dosing and not 24 hours, and the G0s2 and Scd1 were specific for the ciprofibrate suggesting they were involved in a distinct PPARa pathway responsible for the hepatic DNA synthesis. The complete database of the transcriptional response provided here opens doors of opportunity for further research to identify genes...

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“…These differences are similar in extent to those seen in extensive zonation studies on the induction of enzymes by various xenobiotics in isolated rat cells (Oinonen et al, 1994).…”

Section: Section 42 Zonal Distribution Of Dna Synthesis In Liversupporting

confidence: 67%

Mechanism of action of liver growth induced by peroxisome proliferators

Amer

2010

Toxicology

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“…This discrepancy might be explained by species differences in enzyme induction patterns. However, preferential induction of a perivenous P450 isoform in periportal hepatocytes has been reported previously: 3MC leads to the expected perivenous-dominant induction pattern of Cyp1A, whereas administration of another AhR agonist, ␤-naphthoflavone, induces Cyp1A expression in periportal hepatocytes (Wolf et al, 1984;Foster et al, 1986;Bars and Elcombe, 1991;Oinonen et al, 1994). The mechanisms that govern this particular type of enzyme induction are still unknown.…”

Section: Discussionmentioning

confidence: 86%

“…The mechanisms that govern this particular type of enzyme induction are still unknown. It is noteworthy that ␤-naphthoflavone induction of isolated hepatocytes from different zones of the liver could not reproduce the zonal differences observed in vivo (Oinonen et al, 1994). It is therefore likely that regionally acting factors, possibly some not yet identified zonal-specific expressed AhR-associated proteins, modulate periportaland perivenous-specific responses to different AhR agonists, rather than inherent features of certain acinar hepatocyte subpopulations.…”

Section: Discussionmentioning

confidence: 92%

Inducibility of Drug-Metabolizing Enzymes by Xenobiotics in Mice with Liver-Specific Knockout ofCtnnb1

Braeuning

Sanna²,

Huelsken³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Basal as well as xenobiotic-induced expression of the main enzymes from phase I and phase II of drug metabolism is confined to the perivenous areas of the mammalian liver lobule. Whereas signal transduction pathways that govern xenobiotic-induced expression of these enzymes via ligand-activated transcription factors such as constitutive androstane receptor (CAR) or the aryl hydrocarbon receptor (AhR) have been intensively studied, the mechanisms regulating zone-specific basal expression of genes related to drug metabolism and preferential response of perivenous hepatocytes to xenobiotic inducers are still largely unknown. Recent publications by our and other groups point to an important role for the Wnt/␤-catenin pathway in the maintenance of the perivenous hepatocyte gene expression profile including the main hepatic detoxification enzymes, and ␤-catenin signaling was recently implicated in the expression of several cytochrome P450 isoenzymes. To analyze, whether the ␤-catenin pathway would also affect inducible expression of drug-metabolizing enzymes, mice with liverspecific knockout of the Ctnnb1 gene (encoding ␤-catenin) were treated with different model inducers of xenobiotic metabolism. Knockout of ␤-catenin led to alterations in basal expression of most drug metabolism-related genes analyzed and resulted in strongly diminished responses to agonists of CAR-, AhR-, and nuclear factor erythroid-related factor 2-dependent transcription. Taken together, the data presented in this study indicate that ␤-catenin not only regulates basal expression of drug-metabolizing enzymes but also determines the magnitude and hepatic localization of response to xenobiotic inducers in vivo.

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“…The in situ hybridization was performed as described previously (Oinonen et al, 1994). Blocks were sectioned on a cryostat and the sections were placed on slides, which were coated with 3-aminopropyltriethoxysilane and baked at 225°C for 4 hr to inactivate the RNases.…”

Section: In Situ Hybridizationmentioning

confidence: 99%