Study of Biochemical Behavior of Some Exported and
Nonexported Hepatic Proteins during an Acute Inflammatory
Reaction in the Rat

Mahu, Jean-Louis; Feldmann, Gérard

doi:10.1159/000469532

Cited by 11 publications

(5 citation statements)

References 9 publications

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“…The present results demonstrate that 48 h after the induction of an AIR by the s.c. injection of turpentine, the amount and activity of P450 is depressed in hepatocytes by around 50%. These results confirm other studies where it was shown that a turpentine‐induced inflammatory reaction reduced the amount of P450 (Mahu & Feldmann, 1984; Kobusch et al , 1986; Proulx & du Souich, 1995), and decreased in vivo the clearance of tolbutamide and theophylline (Parent et al , 1992; Barakat & du Souich, 1996). In vivo , the serum mediator(s) must play a predominant role in the down‐regulation of the P450 induced by the AIR, since turpentine does not depress directly hepatic P450 (Kobusch et al , 1986).…”

Section: Discussionsupporting

confidence: 92%

“…The serum of rabbits with AIR depressed the P450 of hepatocytes primed by an AIR in 4 h. These results are in agreement with those from a study in mice receiving daily injections of Corynebacterium parvum for 14 days, showing that the administration of endotoxin caused a decrease in hepatic P450 in 90 min (Ghezzi et al , 1986). On the other hand, it has been found that the induction of an AIR by the injection of turpentine or LPS induces a measurable depression of total P450 by 24 h (Mahu & Feldmann, 1984; Morgan, 1989). These apparent contradictions may in fact suggest that the mechanism underlying the down‐regulation of the P450 in primed hepatocytes imply differences in the nature and activity of the serum mediator(s) and/or in the mode of action.…”

Section: Discussionsupporting

confidence: 88%

“…These in vitro results confirm other in vivo studies where it was shown that a turpentine‐induced AIR increased hepatic lipid peroxidation and hepatic xanthine oxidase activity, and decreased the activity of the enzymatic scavengers as well as reduced glutathione (Proulx & du Souich, 1995; Proulx et al , 1995; Barakat & du Souich, 1996). Activation of the immune system by viruses, bacteria, parasites, vaccines, antigens or adjuvants (Renton, 1986), by agents causing a localized inflammatory reaction (Mahu & Feldmann, 1984; Morgan, 1989; Proulx & du Souich, 1995) or by LPS (Morgan, 1989) depress the hepatic P450. The down‐regulation of hepatic P450 has been associated with an increased production of reactive oxygen intermediates.…”

Section: Discussionsupporting

confidence: 83%

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Down‐regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver

El‐Kadi

Maurice

Ong

et al. 1997

British J Pharmacology

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1 Infection and in¯ammation trigger a cascade of mediators that eventually will down-regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute in¯ammatory reaction (AIR) induced by the s.c. injection of turpentine (5 ml), and in the serum of humans with an acute upper respiratory tract viral infection. 2 Hepatocytes from control (H CONT ) rabbits and rabbits with an AIR (H INFLA ) were isolated and cultured. Compared with H CONT in H INFLA the production of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of H INFLA with serum of rabbits with an AIR (RS INFLA ) for 4 h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RS INFLA obtained 6, 12 and 24 h after the injection of turpentine showed the same ability to down-regulate hepatic P450 as the serum obtained at 48 h. 3 The e cacy (E max ) of RS INFLA to inhibit the formation of theophylline metabolites di ered, i.e. 1,3DMU41MU43MX, and the potency of serum mediators (IC 50 ) was similar for 3MX and 1MU, but lower for 1,3DMU. 4 Incubation of serum of human volunteers (HS INFLA ) with a viral infection with H CONT or H INFLA reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HS INFLA depressed 1,3DMU more e ciently than 3MX and 1MU. HS INFLA reduced 3MX with greater e cacy than did RS INFLA . Potency was very variable but not di erent from rabbits. 5 It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HS INFLA or RS INFLA is closely associated with the increase in lipid peroxidation (r 2 = 0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 downregulation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 83%

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Down‐regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver

El‐Kadi

Maurice

Ong

et al. 1997

British J Pharmacology

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“…For example, the ability of the liver to metabolize drugs in rodents is impaired after inflammatory stimuli that are accompanied by a depletion of total hepatic CYP content and a declined microsomal metabolism of drug substrates (57,58). In other similar studies, the experimentally-induced inflammatory reactions resulted in a reduction of the microsomal CYP concentration and their metabolizing activity in the liver (59)(60)(61)(62). In addition, exposure of cultured hepatocytes to inflammatory stimuli decreased the total microsomal CYP, CYP-catalyzed enzyme activities, and levels of CYP proteins and mRNAs (63).…”

Section: Discussionmentioning

confidence: 99%

Respirable Coal Dust Particles Modify Cytochrome P4501A1 (CYP1A1) Expression in Rat Alveolar Cells

Ghanem

Porter²,

Battelli³

et al. 2004

Am J Respir Cell Mol Biol

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Cytochrome P4501A1 (CYP1A1) metabolizes polycyclic aromatic hydrocarbons in cigarette smoke to DNA-binding reactive intermediates associated with carcinogenesis. Epidemiologic studies indicate that the majority of coal miners are smokers but have a lower risk of lung cancer than other smokers. We hypothesized that coal dust (CD) exposure modifies pulmonary carcinogenesis by altering CYP1A1 induction. Therefore, male Sprague Dawley rats were intratracheally instilled with 2.5, 10, 20, or 40 mg CD/rat or vehicle (saline); and 11 d later, pulmonary CYP1A1 was induced by intraperitoneal injection of beta-naphthoflavone (BNF; 50 mg/kg). Fourteen days after CD exposure, CYP1A1 protein and activity were measured by Western blot and 7-ethoxyresorufin-O-deethylase activity, respectively. CYP1A1 and the alveolar type II markers, cytokeratins 8/18, were localized and quantified in lung sections by dual immunofluorescence with morphometry. The area of CYP1A1 expression in alveolar septa and alveolar type II cells in response to BNF was reduced by exposure to 20 or 40 mg CD compared with BNF alone. CD exposure significantly inhibited BNF-induced 7-ethoxyresorufin-O-deethylase activity in a dose-responsive manner. By Western blot, induction of CYP1A1 protein by BNF was significantly reduced by 40 mg CD compared with BNF alone. These findings indicate that CD decreases BNF-induced CYP1A1 protein expression and activity in the lung.

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“…Stimulation of the immune system during an infection or inflammation results in an impairment of hepatic drug metabolism and a decrease in the hepatic content of cytochrome P450, the family of enzymes that are responsible for the metabolism of many drugs and chemical toxins (2)(3)(4). The decrease in drug clearance can result in adverse reactions to normal doses of clinically important drugs, such as theophylline (5), that have low therapeutic indices.…”

mentioning

confidence: 99%

Regulation of Cytochrome P450 2C11 (CYP2C11) Gene Expression by Interleukin-1, Sphingomyelin Hydrolysis, and Ceramides in Rat Hepatocytes

Chen

Nikolova‐Karakashian

Merrill

et al. 1995

Journal of Biological Chemistry

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Interleukin-1 triggers the down-regulation of several hepatic cytochrome P450 gene products, but the cellular signaling pathways involved are not known. We have examined the role of sphingomyelin hydrolysis to ceramide in the suppression of CYP2C11, a major constitutive form of cytochrome P450, by interleukin-1. Treatment of rat hepatocytes cultured on matrigel with interleukin-1␤ caused a rapid turnover of sphingomyelin and an increase in cellular ceramide, with no change in cellular phosphatidylcholine. The ceramide was composed mainly of a D-erythro-sphingosine backbone, suggesting that it was derived from sphingolipid hydrolysis rather than from increased de novo synthesis. Treatment of the cells with either N-acetyl-D-erythro-sphingosine (C 2 -ceramide) or bacterial sphingomyelinase suppressed the expression of CYP2C11 and induced the expression of the interleukin-1-responsive ␣ 1 -acid glycoprotein mRNA. In contrast, the acute-phase gene ␤-fibrinogen, which is induced by interleukin-6 but not by interleukin-1, did not respond to C 2 -ceramide. N-Acetyl-D-erythro-sphinganine mimicked the effect of C 2 -ceramide on CYP2C11, but not on ␣ 1 -acid glycoprotein expression. These results are consistent with a role for ceramide or a related sphingolipid in mediating the down-regulation of CYP2C11, the induction of ␣ 1 -acid glycoprotein, and perhaps other cellular effects of interleukin-1 in hepatocytes.Stimulation of the immune system during an infection or inflammation results in an impairment of hepatic drug metabolism and a decrease in the hepatic content of cytochrome P450, the family of enzymes that are responsible for the metabolism of many drugs and chemical toxins (2-4). The decrease in drug clearance can result in adverse reactions to normal doses of clinically important drugs, such as theophylline (5), that have low therapeutic indices.At least part of the decrease in P450 1 -catalyzed metabolism in response to inflammatory stimuli such as bacterial endotoxin is due to the down-regulation of multiple P450 gene products (6, 7), which appear to be manifested mainly at the transcriptional level (8). The down-regulation of P450 genes is accompanied by a well characterized induction of hepatic plasma proteins (such as fibrinogen and ␣ 1 -acid glycoprotein (9), which are called the "positive acute-phase proteins") and a decreased synthesis of "negative acute-phase proteins" (such as albumin (9)). Cytokines, together with glucocorticoids, are the major humoral mediators of the acute phase of host defense after injury and infection (9). Numerous in vivo and in vitro studies have shown that IL-1␤ plays a key role in inducing many of the acute-phase proteins at both transcriptional and post-transcriptional levels (9), whereas others are induced mainly by the action of interleukin-6 (9). A role for IL-1␤ in the down-regulation of P450 genes has been inferred from several studies in which injection of IL-1␤ in vivo reduced the expression of various P450 gene products (10 -13). However, until now, studies on the mec...

show abstract

Study of Biochemical Behavior of Some Exported and Nonexported Hepatic Proteins during an Acute Inflammatory Reaction in the Rat

Cited by 11 publications

References 9 publications

Down‐regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver

Down‐regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver

Respirable Coal Dust Particles Modify Cytochrome P4501A1 (CYP1A1) Expression in Rat Alveolar Cells

Regulation of Cytochrome P450 2C11 (CYP2C11) Gene Expression by Interleukin-1, Sphingomyelin Hydrolysis, and Ceramides in Rat Hepatocytes

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