Hepatic drug metabolizing enzymes induced by clofibrate in rasH2 mice

Katsutani, Naruo; Sekido, Tohru; Aoki, Toyohiko; Sagami, Fumio

doi:10.1016/s0378-4274(00)00195-8

Cited by 10 publications

(8 citation statements)

References 16 publications

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“…This increase of Tol-Car is in accordance with the reported induction of carnitine acyl transferases (Katsutani et al, 2000) and increases in free carnitine and CoA levels after pretreatment with fibrates (Gregus et al, 1998). Acyl carnitine esters are rarely observed metabolites of xenobiotic carboxylic acids, and to our knowledge, the only xenobiotic carnitine esters that have been previously identified in vivo are the pivaloyl (Vickers et al, 1985;Totsuka et al, 1992), valproyl (Melegh et al, 1990), and zomepirac carnitine esters (Olsen et al, 2005).…”

Section: Discussionsupporting

confidence: 89%

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Olsen

Li²,

Skonberg³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Carboxylic acids may be metabolized to acyl glucuronides and acyl-coenzyme A thioesters (acyl-CoAs), which are reactive metabolites capable of reacting with proteins in vivo. In this study, the metabolic activation of tolmetin (Tol) to reactive metabolites and the subsequent formation of Tol-protein adducts in the liver were studied in rats. Two hours after dose administration (100 mg/kg i.p.), tolmetin acyl-CoA (Tol-CoA) was identified by liquid chromatography-tandem mass spectrometry in liver homogenates. Similarly, the acyl-CoA-dependent metabolites tolmetin-taurine conjugate (Tol-Tau) and tolmetin-acyl carnitine ester (Tol-Car) were identified in rat livers. In a rat bile study (100 mg/kg i.p.), the S-acyl glutathione thioester conjugate was identified, providing further evidence of the formation of reactive metabolites such as Tol-CoA or Tol-acyl glucuronide (Tol-O-G), capable of acylating nucleophilic functional groups. Three rats were treated with clofibric acid (150 mg/kg/day i.p. for 7 days) before dose administration of Tol. This resulted in an increase in covalent binding to liver proteins from 0.9 nmol/g liver in control rats to 4.2 nmol/g liver in clofibric acidtreated rats. Similarly, levels of Tol-CoA increased from 0.6 nmol/g to 4.4 nmol/g liver after pretreatment with clofibric acid, whereas the formation of Tol-O-G and Tol-Tau was unaffected by clofibric acid treatment. However, Tol-Car levels increased from 0.08 to 0.64 nmol/g after clofibric acid treatment. Collectively, these results confirm that Tol-CoA is formed in vivo in the rat and that this metabolite can have important consequences in terms of covalent binding to liver proteins.Drugs with a carboxylate functional group can be metabolized to chemically reactive metabolites that react with nucleophilic amino acids of proteins to form drug-protein adducts (Boelsterli, 2002;Bailey and Dickinson, 2003). Tolmetin (Tol; 5-[4Ј-methylbenzoyl]-1-methylpyrrole-2-acetic acid) is an example of a carboxylic acidcontaining drug which, in humans, is partly metabolized to the acyl glucuronide (Hyneck et al., 1987). In vitro studies have shown that the tolmetin-acyl glucuronide (Tol-O-G) is a reactive metabolite that reacts with the amino acid side chains of lysine, arginine, and serine present in human serum albumin (Ding et al., 1993(Ding et al., , 1995.Covalent binding of Tol has also been studied in humans, where Tol-protein adducts have been detected in plasma (Hyneck et al., 1988;Zia-Amirhosseini et al., 1994). Tol-protein adducts in plasma were believed to result from reaction of the acyl glucuronide with plasma proteins, since a good correlation between covalent plasmaprotein adducts and exposure to Tol-O-G was observed (Hyneck et al., 1988). In the liver, other metabolic pathways may contribute to Tol-protein adduct formation. In a recent study, it has been shown that the pyrrole moiety of Tol may undergo bioactivation to a reactive arene oxide (Chen et al., 2006). Other reports have shown that acyl-coenzyme A thioesters (acyl-CoAs) a...

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Section: Discussionsupporting

confidence: 89%

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Olsen

Li²,

Skonberg³

et al. 2007

Drug Metab Dispos

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“…Moreover, striking analogies in the transcriptome profiles of periportal hepatocytes and Ha-Ras-mutated mouse hepatoma cells indicate an important role of Ras signaling in the regulation of the periportal hepatocyte phenotype [4]. However, transgenic expression of Ha-ras or HGF led to conflicting results: whereas over-expression of HGF or mutant Ha-Ras (in the Tg lox(pA)H-ras* mouse) was effective in blocking basal CYP expression [5,49], two other Ha-Ras-transgenic mice (tg.AC and RasH2) did not show altered CYP expression [42][43][44]46]. In tg.AC mice, expression of the mutant Ha-Ras transgene is under control of the embryo-specific -globin promoter, and, as a consequence, expression of the transgene is lost in adult liver [45].…”

Section: Mapk-mediated Alterations Of Basal Cyp Expression In Murine mentioning

confidence: 82%

“…Decreased expression of several CYPs, especially Cyp2e1, in response to insulin in cultured rat hepatocytes and Fao rat hepatoma cells, as well as enhanced Cyp2e1 mRNA levels after glucagon treatment of hepatocytes have been reported in several articles, in 2b ---HGF activity: testosterone 16 -hydroxylase [49] 2b/2c ---HGF activity: testosterone 6 -hydroxylase [49] 2b9 ---HGF mRNA [49] 2b10 ---HGF mRNA [49] 2c/3a RasH2 human c-Ha-Ras activity: aminopyrine N-demethylase [42] 2c/3a RasH2 human c-Ha-Ras activity: aminopyrine N-demethylase [43] 2c29 ---HGF mRNA, Western blot 1 [49] 2c39 ---HGF mRNA, Western blot 1 [49] 2c50 ---HGF mRNA, Western blot 1 [49] 2c70 ---HGF mRNA, Western blot 1 [49] 2d9 ---HGF mRNA [49] 2d13 ---c-Met knockout mRNA [50] 2d22 ---c-Met knockout mRNA [50] 2e RasH2 human c-Ha-Ras Western blot, activity: aniline hydroxylase [42] 2e RasH2 human c-Ha-Ras Western blot [44] 2e RasH2 human c-Ha-Ras activity: aniline hydroxylase [43] 2e tg.AC v-Ha-Ras Western blot [44] 2e1 tg.AC v-Ha-Ras Western blot [46] 2e1 Tg lox(pA)H-ras* human c-Ha-Ras immunohistochemistry [5] 2g1 ---HGF mRNA [49] 3a RasH2 human c-Ha-Ras Western blot [42] 3a RasH2 human c-Ha-Ras Western blot [44] 3a tg.AC v-Ha-Ras Western blot [44] 3a tg.AC v-Ha-Ras Western blot [46] 3a ---HGF Western blot, activity: testosterone 6 -hydroxylase [49] 3a11 ---HGF mRNA [49] 3a13 ---c-Met knockout mRNA [50] 3a44 ---c-Met knockout mRNA [50] total CYP RasH2 human c-Ha-Ras CO difference spectra [42] total CYP RasH2 human c-Ha-Ras (males only) CO difference spectra [44] total CYP tg.AC v-Ha-Ras CO difference spectra [44] 1 Total Cyp2c protein content was determined by Western blotting without provision for distinct isoforms. Organ: liver, if not otherwise identified.…”

Section: Regulation Of Basal Cytochrome P450 Expres-sion By Egf/ Ras/mentioning

confidence: 83%

“…CYP expression in livers of RasH2 mice carrying a human c-Ha-Ras gene [41] was analyzed by Katsutani and colleagues [42]. No significant differences between the transgenic animals and their wild-type littermates were found for total hepatic CYP content, protein levels of distinct CYP isoforms, and for different CYP-related enzyme activities [42]. Accordingly, CYP activities were comparable between both male and female RasH2 transgenics and the respective wildtype controls [43].…”

Section: Regulation Of Cytochrome P450s By Egf/ Ras/ Mapk Signaling -mentioning

confidence: 99%

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Regulation of Cytochrome P450 Expression by Ras- and β-Catenin-Dependent Signaling

Braeuning

2009

CDM

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Signaling through the Ha-Ras/ mitogen-activated protein kinase cascade and through the Wnt/ beta-catenin signaling pathway has been implicated in various developmental processes as well as in carcinogenesis of different organs by regulating cell growth and differentiation. In particular, both pathways have been reported to play an important role in embryonic liver development as well as in liver regeneration after partial hepatectomy. More recently, there is accumulating evidence for a role of Ras- and beta catenin-dependent signal transduction in the regulation of zone-specific gene expression in healthy adult liver. An antagonistic interplay of both pathways was proposed: beta-catenin was established to function as a decisive regulator of 'perivenous' gene expression in hepatocytes neighboring branches of the central vein, whereas the Ras pathway was linked to transcription of 'periportal' genes. Xenobiotic-metabolizing enzymes constitute one of the largest functionally related groups of zonated genes with predominantly perivenous expression of the most abundant enzymes of xenobiotic metabolism. In this review, the current knowledge regarding the role of Ras and beta catenin signaling in the regulation of expression of xenobiotic-metabolizing enzymes from the cytochrome P450 superfamily will be summarized including both in vitro and in vivo observations.

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“…Further, in a comparison of levels of drug-metabolizing enzymes between transgenic or knockout mice and their parental strains using Western immunoblotting, increased expression of CYP2B and CYP3A isoforms was evident in XPA gene knockout mice with no differences from parental strains for rasH2, p53(þ/-), and Tg.AC mice (Ariyoshi et al 2001). Clofibrate-treated rasH2 mice had a similar increased content and activity of P450 as their wildtype littermates (Katsutani et al 2000). Lastly, induction of CYP2B, 2C, and 3A was evaluated immunochemically by immunoblotting in male and female patas and cynomologus monkeys treated with phenobarbital (Jones and Lubet 1992).…”

Section: Species Sex and Strain Differences In Enzyme Inductionmentioning

confidence: 99%

Hepatic Enzyme Induction

et al. 2010

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Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents, infections associated with acute-phase proteins, as well as responses to exposure to xenobiotics. Common xenobiotic enzyme inducers trigger pathways involving the constitutive androstane receptor (CAR), the peroxisome proliferator-activated receptor (PPAR), the aryl hydrocarbon receptor (AhR), and the pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia. The hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific xenobiotics.

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Hepatic drug metabolizing enzymes induced by clofibrate in rasH2 mice

Cited by 10 publications

References 16 publications

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Regulation of Cytochrome P450 Expression by Ras- and β-Catenin-Dependent Signaling

Hepatic Enzyme Induction

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Hepatic drug metabolizing enzymes induced by clofibrate in rasH2 mice

Cited by 10 publications

References 16 publications

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Regulation of Cytochrome P450 Expression by Ras- and &#946;-Catenin-Dependent Signaling

Hepatic Enzyme Induction

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Regulation of Cytochrome P450 Expression by Ras- and β-Catenin-Dependent Signaling