Up-regulation of CYP2A5 expression by porphyrinogenic agents in mouse liver

Salonpää, Pirkko; Krause, Kai; Pelkonen, Olavi; Raunio, Hannu

doi:10.1007/bf00169087

Cited by 28 publications

(22 citation statements)

References 30 publications

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“…Ratanasavanh et al (1996) also found that the metabolic rate of coumarin decreases in primary hepatocyte cultures from both man, rat and mice during the first 24 hr in culture. In the present study the same decrease was seen in cultures exposed to pyrazole, although pyrazole has been reported to be an inducer of coumarin 7-hydroxylase activity catalyzed by CYP2A5 in mouse primary hepatocytes (Kojo et al 1998) and in mouse livers after in vivo treatment with pyrazole (Salonpää et al 1995). Rifampicin did not induce the coumarin 7-hydroxylase activity either.…”

Section: Discussionsupporting

confidence: 74%

Expression Changes of CYP2A and CYP3A in Microsomes from Pig Liver and Cultured Hepatocytes

Skaanild¹,

Friis²

2000

Pharmacology & Toxicology

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The P450 enzymes of the liver are responsible for the metabolism of a wide range of chemical compounds, and hepatocytes are used in pharmacological and toxicological in vitro tests. Thus, it is important to know how stable these enzymes are in culture. We measured the activity of CYP2A and CYP3A in microsomes isolated from both pig liver and primary pig hepatocyte cultures, together with the apoprotein concentration using Western blotting. The CYP2A activity and apoprotein concentration decreased rapidly; only about 5 percent remained after 48 hr incubation, whereas the CYP3A activity and apoprotein concentration was constant. CYP3A was induced 3 times after exposure to rifampicin, whereas neither rifampicin nor pyrazole could induce CYP2A. The hepatocytes were also incubated with varying concentration of FCS and autologous serum, however without effect on the stability of CYP2A, nor did different concentrations of growth hormone and testosterone added to the cultures have any effect.The P450 enzymes are involved in the oxidation of a wide range of compounds including drugs, steroids, vitamins etc. (Nelson et al. 1996). The action of P450 may lead to eventual detoxification of the substrate, either direct or through the subsequent action of phase 2 enzymes. However the activity of P450 can also produce toxic metabolites. Because of these unique functions of the liver, cultured hepatocytes and microsomes from hepatocytes and livers have been used for toxicological and metabolic studies in vitro. Several studies show a decrease in enzyme activity of some of the cytochrome P450 isoenzymes. These declines have been observed in both human (George et al. 1996;Vandenbranden et al. 1998) and rat (Liddle et al. 1992) primary hepatocytes cultures. It is therefore essential to establish how pig hepatocytes P450 react in cultures, especially if pig hepatocytes are used as a substitute for i.e. human hepatocytes in toxicological and pharmacological in vitro studies. It is important to know if the P450 isoenzymes remain active and in the same proportions in microsomes isolated from liver and cultured hepatocytes. Since preliminary studies in our laboratory indicate that CYP2A in pig hepatocytes decrease very fast after start of culture, the objectives of this study were: 1) to measure and compare the activity and the immunochemical level of two isoenzymes CYP2A and CYP3A in microsomes from livers, from freshly isolated hepatocytes and from hepatocytes cultured up to 48 hr, 2) to investigate the inducibility of CYP2A and CYP3A with classical inducers, 3) to analyze if serum contains ''stimulating factors'' for the activity of the two isoenzymes, and 4) Author for correspondence: Mette T. Skaanild, The Royal Veterinary and Agricultural University, Department of Pharmacology and Pathobiology, Ridebanevej 9, DK-1870 Frederiksberg C, Denmark (fax π45 35 35 35 14, e-mail mts/kvl.dk). the effect of growth hormone and testosterone exposure was also studied. Materials and MethodsThe experiment was performed using female Dani...

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Section: Discussionsupporting

confidence: 74%

Expression Changes of CYP2A and CYP3A in Microsomes from Pig Liver and Cultured Hepatocytes

Skaanild¹,

Friis²

2000

Pharmacology & Toxicology

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“…The increased expression of Cyp2a4 observed here may be a cross hybridiation with Cyp2a5 known to be increased in expression during the development of liver injury and hepatocarcinomas (Camus-Randon et al 1996;Knasmuller et al 1997;Salonpaa et al 1995;Wastl et al 1998) and is also induced directly by porphyrinogenic agents (Salonpaa et al 1995). The most highly upregulated Cyp genes in this set, Cyp2b9, Cyp2b10, and Cyp2b13, were increased in expression up to 100-fold.…”

Section: Toxicogenomics | Gant Et Alsupporting

confidence: 49%

Gene expression profiles associated with inflammation, fibrosis and cholestasis in mouse liver after griseofulvin

Gant¹,

Baus²,

Clothier³

et al. 2002

Environ. Health Perspect. Toxicogenomics

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Erythropoietic protoporphyria patients can develop cholestasis, severe hepatic damage, fibrosis, and cirrhosis. We modeled this hepatic pathology in C57BL/6J and BALB/c mice using griseofulvin and analyzed 3,127 genes for alteration of expression in the liver before and during the onset of protoporphyria, cholestasis, inflammation, and hepatic fibrosis. The two mouse strains developed different levels of pathologic damage in response to the griseofulvin. Characteristic gene expression profiles could be associated with griseofulvin-induced gene expression, disruption of lipid metabolism, and the pathologic states of inflammation, early fibrosis, and cholestasis. Additionally, some genes individually indicated an alteration of homeostasis or pathologic state; for example, fibroblast proliferation was potentially indicated by increased calcyclin (SA100a6) expression. Changes in cytochrome P450 (Cyp) gene expression were particularly pronounced, with increased expression of the Cyp2a, Cyp2b, and Cyp3a families. Decreased Cyp4a10 and Cyp4a14 expression was observed that could be associated with early pathologic change. A potential decrease in bile acid and steroid biosynthesis was indicated by the decreased expression of Cyp7b1 and Hsd3b4, respectively. DNA damage was indicated by induction of GADD45. This study illustrates how transcriptional programs can be associated with different stimuli in the same experiment. The time course of change in the gene expression profile compared with changes in pathology and clinical chemistry shows the potential of this approach for modeling causative, predictive, and adaptive changes in gene expression during pathologic change.

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“…The latter has been associated with porphyria, liver injury, and hepatic tumors. [33][34][35] Western blotting confirmed the marked presence of CYP2A5 protein in livers of 26-week mice and hepatic adenoma tissue (Figure 4e). Changes in gene expressions associated with hepatocyte bile acid up-take, lymphocyte infiltration, remodeling, cirrhosis, and proliferation in older mice were mainly significantly less or absent in the 4-week-old mice com- Values represent means Ϯ of three to five mice.…”

Section: Modulation Of Expression With Agementioning

confidence: 64%

Hepatic Gene Expression in Protoporphyic Fech Mice Is Associated with Cholestatic Injury but Not a Marked Depletion of the Heme Regulatory Pool

Davies

Schuurman

Barker

et al. 2005

The American Journal of Pathology

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BALB/c Fech m1Pas mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism Heme is vital to the transport and utilization of oxygen in oxidative and signaling pathways. A large proportion of heme usage in the liver is accounted for by cytochrome P450 isoforms, many of which are associated with drug metabolism. In the final step of heme synthesis ferrous iron is inserted into the precursor porphyrin protoporphyrin IX by the mitochondrial enzyme ferrochelatase. The structure and regulation of ferrochelatase have been extensively studied.

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Up-regulation of CYP2A5 expression by porphyrinogenic agents in mouse liver

Cited by 28 publications

References 30 publications

Expression Changes of CYP2A and CYP3A in Microsomes from Pig Liver and Cultured Hepatocytes

Expression Changes of CYP2A and CYP3A in Microsomes from Pig Liver and Cultured Hepatocytes

Gene expression profiles associated with inflammation, fibrosis and cholestasis in mouse liver after griseofulvin

Hepatic Gene Expression in Protoporphyic Fech Mice Is Associated with Cholestatic Injury but Not a Marked Depletion of the Heme Regulatory Pool

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