Liver Injury and Expression of Cytochromes P450: Evidence That Regulation of CYP2A5 Is Different from That of Other Major Xenobiotic Metabolizing CYP Enzymes

Camus-Randon, Anne-Marie; Raffalli, F; Béréziat, Jean‐Claude; McGregor, Douglas; Konstandi, Maria; Lang, Matti A.

doi:10.1006/taap.1996.0107

Cited by 48 publications

(37 citation statements)

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“…The relationship between pyrazole treatment, hepatocellular injury and CYP2A5 induction demonstrated in this study is consistent with observations in other mouse models of hepatotoxicity (Camus-Randon et al, 1996) and hepatitis (Chemin et al, 1996). Several investigators have shown that CYP2A5 induction occurs during the early stages of hepatocellular injury and is not associated with terminal forms of injury such as necrosis (Arvela et al, 1991) or apoptosis (Tetri et al, 2002).…”

Section: Discussionsupporting

confidence: 91%

“…Cytochrome P450 2a5 (CYP2A5) is induced by a diverse array of hepatotoxins, including nitrogen heterocycles (Kojo et al, 1998), chlorinated hydrocarbons (Camus-Randon et al, 1996), metal ions (Hahnemann et al, 1992), and porphyrinogenic agents (Donato et al, 2000), which are neither structurally similar nor generally considered to be inducers of P450s. Moreover, CYP2A5 is induced during viral (Kirby et al, 1994a), fulminant (Chemin et al, 1996), bacterial (Sipowicz et al, 1997), and parasitic hepatitis (Kirby et al, 1994b), pathophysiological conditions that are usually associated with suppression of P450s.…”

mentioning

confidence: 99%

“…Moreover, CYP2A5 is induced during viral (Kirby et al, 1994a), fulminant (Chemin et al, 1996), bacterial (Sipowicz et al, 1997), and parasitic hepatitis (Kirby et al, 1994b), pathophysiological conditions that are usually associated with suppression of P450s. Most studies to date have focused on identifying specific inducers of CYP2A5; however, it is increasingly apparent that induction is not directly related to the nature of the inducing agents but may be an indirect consequence of a specific cellular event associated with the pathogenesis of liver injury (Camus-Randon et al, 1996).…”

mentioning

confidence: 99%

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Endoplasmic Reticulum Stress Due to Altered Cellular Redox Status Positively Regulates Murine Hepatic CYP2A5 Expression

Gilmore¹,

Kirby²

2003

J Pharmacol Exp Ther

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Murine hepatic cytochrome P450 2A5 (CYP2A5) is uniquely induced by a variety of agents that cause liver injury and inflammation, conditions that are typically associated with downregulation of P450s. We hypothesized that induction of CYP2A5 occurs in response to hepatocellular damage resulting in endoplasmic reticulum (ER) stress. Treatment of mice in vivo and mouse hepatocytes in primary culture with the CYP2A5 inducer pyrazole resulted in overexpression of the ER stress biomarker glucose-regulated protein (GRP) 78. Treatment of primary hepatocytes with ER stress activators thapsigargin, tunicamycin, and trans-4,5-dihydroxy-1,2-dithiane (DTT ox ) and the calcium ionophore A23187 (calcimycin) resulted in elevated GRP78 mRNA levels; however, only the reducing agent DTT ox induced levels of CYP2A5 mRNA, protein, and coumarin 7-hydroxylase activity. To test the hypothesis that CYP2A5 induction is due to liver injury resulting from altered cellular redox status, we demonstrated that CYP2A5 induction, elevated serum alanine aminotransferase, and oxidative protein damage occur concurrently in pyrazole-treated mice. Pyrazole also induced the expression of cytosolic ␣ and class glutathione S-transferase expression both in vivo and in primary mouse hepatocytes. Moreover, treatment of hepatocytes with the redox cycling quinone menadione resulted in overexpression of CYP2A5 and GSTM1 mRNA. Finally, pretreatment of hepatocytes with the antioxidants N-acetylcysteine and vitamin E attenuated pyrazole-mediated increases in CYP2A5 mRNA levels. These findings clearly indicate that induction of mouse hepatic CYP2A5 during liver injury occurs via a novel mechanism involving ER stress due to altered cellular redox status.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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confidence: 99%

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Endoplasmic Reticulum Stress Due to Altered Cellular Redox Status Positively Regulates Murine Hepatic CYP2A5 Expression

Gilmore¹,

Kirby²

2003

J Pharmacol Exp Ther

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“…Unfortunately, the present understanding of this critical issue is extremely limited. Increased expression of CYP2E1 and CYP2A5 was observed in TAA-induced liver injury models (Camus-Randon et al, 1996;Avni et al, 2003); a previous report showed that nicotine metabolism was significantly decreased in the TAA-induced fibrotic rat livers, associated with the down-regulated protein levels of most P450s (Nakajima et al, 1998). However, TAA-induced potential regulation of enzyme activity of P450s remains unclear.…”

Section: Introductionmentioning

confidence: 94%

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Xie¹,

Wang²,

Wang³

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.

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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 Almentioning

confidence: 74%

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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Liver Injury and Expression of Cytochromes P450: Evidence That Regulation of CYP2A5 Is Different from That of Other Major Xenobiotic Metabolizing CYP Enzymes

Cited by 48 publications

References 0 publications

Endoplasmic Reticulum Stress Due to Altered Cellular Redox Status Positively Regulates Murine Hepatic CYP2A5 Expression

Endoplasmic Reticulum Stress Due to Altered Cellular Redox Status Positively Regulates Murine Hepatic CYP2A5 Expression

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

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

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