Gene Expression Changes Associated with the Endoplasmic Reticulum Stress Response Induced by Microsomal Cytochrome P450 Overproduction

Szczesna-Skorupa, Elzbieta; Chen, Ci Di; Liu, Hong; Kemper, Byron

doi:10.1074/jbc.m312170200

Cited by 52 publications

(55 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A function of SER is to hold the enzymes in the hepatocytes that synthesize steroid hormones, metabolize endogenous and exogenous substrates, synthesize glucose as well as perform other related functions. The overexpression of microsomal P450s (fatty acid ω-hydroxylases) typically results in extensive proliferation of SER (Szczesna-Skorupa et al, 2004) In our studies we observed significant increases in the expression of CYP4A12. Rat CYP4A proteins possess fatty acid ω-hydroxylase activities (Su et al, 2005), thus linking induction of CYP4A proteins and hepatic hypertrophy by triadimefon.…”

Section: Hepatic Hypertrophysupporting

confidence: 66%

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

et al. 2006

View full text Add to dashboard Cite

Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230 2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish triadimefon from propiconazole and myclobutanil.

show abstract

Section: Hepatic Hypertrophysupporting

confidence: 66%

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Oxidative stress was most likely induced by the increased accumulation of lipids, as well as by the overproduction of P450 enzymes. Most interestingly, the expression of several heat shock proteins was reduced in both liver-Cpr-null and Cpr-low mice, a feature that distinguishes the observed stress response from the gene expression changes induced by endoplasmic reticulum stress caused by CYP2C2 overproduction in cultured cells (74). Induction of enzymes in amino acid metabolism and decreases in fatty acid-binding protein were found in both studies, but heat shock proteins were induced by endoplasmic reticulum stress in HepG2 cells overexpressing P450 (74).…”

Section: Table Imentioning

confidence: 94%

Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene

Weng

DiRusso

Reilly

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferatoractivated receptor-␣ by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid translocase (Cd36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (Cpt1a) and acyl-CoA synthetase long chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis and an altered fatty acid profile observed in liver-Cprnull mice.

show abstract

“…Because cell lines express extremely low levels of CYP3A4, we use an adenovirus transduction system that has been previously used to successfully increase CYP3A4 expression in human cell lines (Brimer et al, 2000). Care must be taken, though, because overexpression of some P450 proteins can stimulate an ER stress response that includes activation of the NF-B pathway (Szczesna-Skorupa et al, 2004), a result that could confound our studies. Therefore, CYP3A4 protein in the HepG2 cells was kept at a level that is only a small fraction of normal human hepatic levels.…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Factor-κB Pathway Regulates Cytochrome P450 3A4 Protein Stability

Zangar¹,

Bollinger²,

Verma³

et al. 2008

Mol Pharmacol

View full text Add to dashboard Cite

We have previously observed that CYP3A4 protein levels are suppressed by inhibition of the proteasome in primary cultured hepatocytes. Because this result is opposite of what would be expected if CYP3A4 were degraded by the proteasome, it seemed likely that there might be another protein susceptible to proteasomal degradation that regulated CYP3A4 expression. In this study, we evaluated whether the nuclear factor-B (NF-B) pathway was involved in that process. Our model system used an adenovirus system to express CYP3A4 protein in HepG2 cells, which are derived from human cancer cells. Similar to results in primary hepatocytes, the inhibition of the proteasome with N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) suppresses CYP3A4 protein levels. We also found that MG132 treatment had a broad affect on the NF-B pathway, including down-regulation of NF-B DNA binding activity and IB kinase (IKK)␣ levels and up-regulation of IKK␤ and inhibitory B levels. Treatment of the HepG2 cells with several structurally distinct NF-B inhibitors also suppressed CYP3A4 protein levels. When the HepG2 cells were treated with cycloheximide, a general inhibitor of protein synthesis, the loss of CYP3A4 protein was accelerated by cotreatment with either proteasome or NF-B inhibitors. These results indicate that NF-B activity regulated CYP3A4 protein stability, and they suggest that the NF-B pathway was responsible for the decrease in CYP3A4 protein levels that resulted from the proteasomal inhibition.

show abstract

Gene Expression Changes Associated with the Endoplasmic Reticulum Stress Response Induced by Microsomal Cytochrome P450 Overproduction

Cited by 52 publications

References 49 publications

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene

The Nuclear Factor-κB Pathway Regulates Cytochrome P450 3A4 Protein Stability

Contact Info

Product

Resources

About