Signal transduction pathways implicated in the decrease in CYP1A1, 1A2 and 3A6 activity produced by serum from rabbits and humans with an inflammatory reaction

Levitchi, Mihaela; Fradette, Caroline; Bleau, Anne-Marie; Michaud, Dorothée; Kourylko, Oksana; Arcand, Mathieu; Souich, Patrick du

doi:10.1016/j.bcp.2004.04.002

Cited by 8 publications

(8 citation statements)

References 56 publications

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“…Cytokines and potentially growth factors may induce NO synthase expression and, therefore, may be responsible for high NO levels found in regenerative livers. NO was shown to inactivate P450 enzyme activity by binding to the P450 protein (Levitchi et al, 2004). In this study, we did not detect an increased NO release into the culture medium during ALR treatment.…”

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confidence: 65%

“…The responsible mechanisms are not known yet, but for a likely transcriptional or posttranscriptional regulation, either an activation of P450 genes or an altered rate of mRNA degradation might be necessary as proposed for the P450 enzyme regulation by EGF and HGF (Muntane-Relat et al, 1995;Donato et al, 1998). Furthermore, several authors have suggested that the production of nitric oxide (NO) leads to down-regulation of P450 enzyme activities after inflammation or tissue injury (Levitchi et al, 2004). Cytokines and potentially growth factors may induce NO synthase expression and, therefore, may be responsible for high NO levels found in regenerative livers.…”

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confidence: 99%

“…Using different inhibitors of signaling pathways, they could demonstrate that the activation of protein tyrosine kinases and p42/44 mitogen kinase are involved in P450 repression (Levitchi et al, 2004). On the other hand, it was reported that ALR upon binding to its own specific receptor (Wang et al, 1999) acts through stimulation of the tyrosine phosphorylation of the epidermal growth factor receptor and activates the MAPK cascade indicated by phosphorylated MAPK kinase and extracellular signal-regulated kinase (p42/44 mitogen kinase) (Li et al, 2000).…”

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Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Thasler

Dayoub²,

Mühlbauer³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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Pathological disorders of the liver were shown to be associated with an impairment of hepatic drug metabolism mediated in part by growth factors. Augmenter of liver regeneration (ALR) is a novel liver-specific hepatotrophic growth factor, whereas its action on cytochrome P450 (P450) metabolism is completely unknown. Application of ALR to primary human hepatocytes in vitro reduced P450 isoenzyme activities (1A2 and 2A6) in a dose-dependent manner. Time-course analysis revealed that the maximal inhibitory effect was reached after 24 to 72 h of exposure with 50 nM ALR. The reduction of basal activities upon ALR treatment was 35% for CYP1A2, 56% for CYP2A6, 18% for CYP2B6, and 45% for CYP2E1. Additionally, after induction of P450 with specific inducers, ALR revealed an inhibitory effect on the isoenzyme activities (CYP1A2, 41%; CYP2B6, 35%). Investigations of protein and mRNA expression of basal and induced CYP1A2 and CYP3A4 after ALR treatment by Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively, suggest a regulation on the transcriptional level. Furthermore, ALR treatment increased nuclear factor kB activity and reduced constitutive androstane receptor but not pregnane X receptor or aryl hydrocarbon receptor expression. In contrast, ALR revealed no effects on phase II reactions (glutathione/oxidized glutathione, UDP-glucuronyltransferase conjugation). Our results indicate that ALR, as a member of hepatotrophic factors, down-regulates basal and induced P450 in human liver and therefore cross-links growth signals to regulation of hepatic metabolism. These findings further imply a possible role of ALR in drug interactions during impaired hepatic function, whereas liver regeneration is triggered.

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confidence: 65%

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Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Thasler

Dayoub²,

Mühlbauer³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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“…The activity of CYP3A6 was assessed by measuring the ability of the hepatocytes to convert 3,4-difluorobenzyloxy-5,5-dimethyl-4-(4-methylsulfonyl phenyl)-(5H)-furan-2-one (DFB), a CYP3A substrate, to 3-hydroxy-4-(4-methylsulfonyl phenyl)-(5H)-furan-2-one (DFH), its fluorescent metabolite (Levitchi et al, 2004). After 4 and 24 h of incubation, the growth medium was removed, and hepatocytes were washed twice with 300 l of Krebs' solution.…”

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confidence: 99%

“…Actually, it is known that, in vivo and in vitro, the down-regulation of P450 isoforms is preceded by a decrease in activity that is mediated primarily by IL-6, IL-1␤ and interferon-␥ (El- Kadi et al, 1997;Bleau et al, 2000;Barakat et al, 2001). This post-translational reduction in P450 activity is still not well understood, but has been associated with reversible inhibitory effects of reactive oxygen species (ROS) and nitric oxide (NO ⅐ ) (Takemura et al, 1999;El-Kadi et al, 2000), and implicates the activation of extracellular signal-related kinases (Erk1/2) and protein kinase C (Levitchi et al, 2004).…”

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confidence: 99%

Modulation of Cyp1a2 and Cyp3a6 Catalytic Activities by Serum From Rabbits With a Turpentine-Induced Inflammatory Reaction and Interleukin 6

Kourylko

Fradette²,

Arcand³

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:Inflammatory reactions reduce the activity of cytochrome P450 isoforms. The aim of the study was to determine the mechanisms underlying the decrease in CYP1A2 and CYP3A6 catalytic activities produced by serum from rabbits with a turpentine-induced inflammatory reaction (S TIIR ) and interleukin 6 (IL-6). S TIIR and IL-6 were incubated with cultured primary hepatocytes from control rabbits (H CONT ), and from rabbits with a turpentine-induced inflammatory reaction (H TIIR ) in the absence or presence of pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of nuclear factor B transcription; 2-amino-3-methoxyflavone (PD98059), an inhibitor of extracellular signal-related kinase (Erk1/2); 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), an inhibitor of p38MAPK; N -nitro-L-arginine methyl ester, an inhibitor of nitric-oxide synthase 2 (NOS2); the combination of PDTC, PD98059, and SB203580; and genistein, an inhibitor of Janus-associated protein tyrosine kinase (JAK). After 4 and 24 h of incubation of H CONT with S TIIR and IL-6, CYP1A2 activity was reduced without changes in expression; the reduction in activity was partially prevented by the inhibition of JAK, Erk1/2, and NOS2. In H CONT , S TIIR and IL-6 did not affect CYP3A6 activity; however, PDTC reduced CYP3A6 activity by 40 and 80% after 4 and 24 h of incubation. In H TIIR , S TIIR and IL-6 reduced both CYP1A2 and CYP3A6 activities; this decrease is partially prevented by inhibitors of protein tyrosine kinases, Erk1/2, and NOS2. In H TIIR , SB203580 increased CYP3A6 activity in a dose-dependent manner without changes in protein expression. These results show that the signal transduction pathways mediating the decrease in CYP1A2 and 3A6 activity, produced by S TIIR and IL-6, involve JAK, Erk1/2, and NOS2.There is considerable evidence that in humans an inflammatory reaction can diminish the activity of the cytochrome P450 (P450) superfamily . The first documented observation reported that an upper respiratory viral infection in asthmatic children increased theophylline plasma concentrations and half-life (Chang et al., 1978). Actually, numerous reports have documented that influenza infections reduce the rate of biotransformation of theophylline and other drugs (Cheng and Morgan, 2001;Renton, 2001). Moreover, bacterial respiratory infections, as well as chronic obstructive lung disease, reduce the ability of the organism to clear xenobiotics (Sonne et al., 1985). Other causes of inflammation, such as elective surgery, reduce the activity of CYP3A4 (Haas et al., 2003). Using animal models, it has been shown that various models of inflammation, such as the injection of lipopolysaccharide (LPS), turpentine, and carrageenan depress the activity of the P450 (Cheng and Morgan, 2001;Renton, 2001).Already in 1978, the decrease in theophylline clearance was attributed to the down-regulation of P450 isoforms (Renton, 1978). Since then, many reports have confirmed that an inflammatory reaction triggers the release of...

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The 21-aminosteroid U74389G prevents the down-regulation and decrease in activity of CYP1A1, 1A2 and 3A6 induced by an inflammatory reaction

Taherzadeh

Fradette

Bleau

et al. 2006

Biochemical Pharmacology

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Signal transduction pathways implicated in the decrease in CYP1A1, 1A2 and 3A6 activity produced by serum from rabbits and humans with an inflammatory reaction

Cited by 8 publications

References 56 publications

Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Repression of Cytochrome P450 Activity in Human Hepatocytes in Vitro by a Novel Hepatotrophic Factor, Augmenter of Liver Regeneration

Modulation of Cyp1a2 and Cyp3a6 Catalytic Activities by Serum From Rabbits With a Turpentine-Induced Inflammatory Reaction and Interleukin 6

The 21-aminosteroid U74389G prevents the down-regulation and decrease in activity of CYP1A1, 1A2 and 3A6 induced by an inflammatory reaction

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