Binding characteristics of 4‐S proteins from rat and mouse liver High affinity of ellipticines

Roy, Marianne; Fernández, Nadia; Lesca, P.

doi:10.1111/j.1432-1033.1988.tb13930.x

Cited by 24 publications

(8 citation statements)

References 18 publications

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“…The incubation of radiolabelled BP with rat liver cytosolic protein also resulted in specific binding of protein as determined by co-incubation with unlabelled BP. The level of specific binding of radiolabelled BP with increasing concentrations of radio- are in agreement with previous studies [18,52]. By employing a fixed concentration of radiolabelled BP, it can be seen that metyrapone significantly reduced the levels of binding of BP to cytosolic protein in a concentration-dependent manner and in excess of any effects on non-specific binding of BP (Table 1).…”

Section: Examination Of the Ability Of Metyrapone To Compete With Thesupporting

confidence: 91%

Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone

Harvey¹,

Paine²,

Wright³

1998

Biochemical Journal

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The transcriptional induction of the cytochrome P-450 1A1 (CYP1A1) gene by xenobiotics such as polyaromatic hydrocarbons is dependent on their interaction with the aryl hydrocarbon receptor. Administration of the structurally unrelated compounds metyrapone (a cytochrome P-450 inhibitor) or dexamethasone (a glucocorticoid) to male rats does not induce hepatic CYP1A1 mRNA. However, administration of both metyrapone and dexamethasone to male rats results in the induction of hepatic CYP1A1 mRNA expression. The induction response is mimicked in vitro in cultured rat hepatocytes by the addition of metyrapone and dexamethasone to a serum-free culture medium, suggesting that these compounds act directly on the liver in vivo to effect hepatic CYP1A1 mRNA induction. An examination of the characteristics of CYP1A1 induction by metyrapone and dexamethasone in combination in vitro indicate that at least 6 h of treatment is required for detectable levels of CYP1A1 mRNA to accumulate in hepatocytes. In contrast, beta-naphthoflavone, which is known to bind to the aryl hydrocarbon receptor to effect CYP1A1 gene expression, induces detectable levels of CYP1A1 mRNA within 2 h of treatment. CYP1A1 mRNA is also induced when hepatocytes are treated with metyrapone in combination with the protein synthesis inhibitor cycloheximide but not with dexamethasone in combination with cycloheximide, indicating that CYP1A1 mRNA induction is strictly dependent on the presence of metyrapone and suggesting that the metyrapone-associated induction of CYP1A1 mRNA is dependent on a loss of a constitutively expressed protein that functions to suppress CYP1A1 gene expression. The role of dexamethasone in metyrapone-associated induction of CYP1A1 is probably mediated through the glucocorticoid receptor since the glucocorticoid receptor antagonist RU486 reduces the levels of CYP1A1 mRNA induced by metyrapone and dexamethasone in combination. Increasing the levels of the photosensitizer riboflavin present in the culture medium 10-fold and exposure to light increases the levels of CYP1A1 mRNA induced by metyrapone and dexamethasone in combination in vitro, suggesting that photoactivation of inducing medium constituent(s) might be required for induction. Failure to induce CYP1A1 mRNA by co-administration of metyrapone and dexamethasone in hepatocytes cultured in a balanced salt solution with or without photoactivation indicates that induction is dependent on a photoactivated component of the culture medium and not on metyrapone or dexamethasone alone. The addition of tryptophan in the presence of riboflavin to the balanced salt solution restores CYP1A1 mRNA induction by metyrapone alone and induction is increased when medium is exposed to light, indicating that induction is dependent on tryptophan photoactivation in vitro. Metyrapone failed to compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin for specific binding to the aryl hydrocarbon receptor in rat liver cytosolic fractions. These results suggest that CYP1A1 might be induced in rats by metyrapone through ...

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Section: Examination Of the Ability Of Metyrapone To Compete With Thesupporting

confidence: 91%

Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone

Harvey¹,

Paine²,

Wright³

1998

Biochemical Journal

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“…βNF has been also shown to bind to AhR in the cytosol of rat liver cells with an affinity less than that of TCDD and greater or similar to that of benzo[a]pyrene (Roy et al, 1988). PFTα and PFTβ were able to induce enzymatic AhR mediated responses in vitro, without significant differences between them at all dose levels in both cell systems, indicating the ability of these xenobiotics to activate the AhR.…”

Section: Discussionmentioning

confidence: 96%

Biological and chemical studies on aryl hydrocarbon receptor induction by the p53 inhibitor pifithrin-α and its condensation product pifithrin-β

et al. 2011

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“…The finding that S 16020 is a substrate and inducer of CYP1As was expected from its chemical planar structure (Gasiewicz et al, 1996). In fact, this compound is structurally related to ellipticine, which has been characterized for a long time as an aryl hydrocarbon-like inducer (Lesca et al, 1976;Phillipson et al, 1982), although it becomes an antagonist of AhR at high concentrations Roy et al, 1988;Gasiewicz et al, 1996). In addition, ellipticine is known to be an inhibitor and presumably a substrate of CYP1As (Lesca et al, 1978(Lesca et al, , 1979(Lesca et al, , 1980(Lesca et al, , 1981Delaforge et al, 1980;Cresteil et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

THE OLIVACINE DERIVATIVE S 16020 (9-HYDROXY-5,6-DIMETHYL-N-[2-(DIMETHYLAMINO)ETHYL)-6H-PYRIDO(4,3-B)-CARBAZOLE-1-CARBOXAMIDE) INDUCES CYP1A AND ITS OWN METABOLISM IN HUMAN HEPATOCYTES IN PRIMARY CULTURE

Pichard-Garcia

Weaver²,

Eckett³

et al. 2004

Drug Metab Dispos

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ABSTRACT:The olivacine derivative 9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-b)-carbazole-1-carboxamide (S 16020) exhibits a potent antitumor activity. However, when administered in cancer patients, its blood clearance increases after repeated administrations, whereas the volume of distribution remains constant, suggesting that the drug is able to induce its own metabolism. The aim of this work was to identify the enzymes involved in S 16020 metabolism and determine whether this molecule is an enzyme inducer in human hepatocytes in primary cultures. Among a battery of cDNA-expressed cytochromes P450 (P450s) and flavin monooxygenase (FMO), only CYP1A1, CYP1A2, and FMO3 were able to generate detectable amounts of metabolites of S 16020. In primary hepatocytes, S 16020 behaved as a CYP1A inducer, producing an increase in CYP1A2 protein, acetanilide 4-hydroxylation, ethoxyresorufin O-deethylation, and chlorzoxazone 6-hydroxylation to an extent similar to that of 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), a prototypical CYP1A inducer. The levels of other P450 proteins, including CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, and related activities were not affected by S 16020. In primary hepatocytes, pretreatment of cells with S 16020 or TCDD produced a significant and similar increase of S 16020 metabolism, consistent with the previous indications on the role of CYP1As. We conclude that CYP1As and FMO3 are the major phase I enzymes involved in the metabolism of S 16020 and that this molecule is a potent hydrocarbon-like inducer able to stimulate its own metabolism in primary human hepatocytes and liver.

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Binding characteristics of 4‐S proteins from rat and mouse liver High affinity of ellipticines

Cited by 24 publications

References 18 publications

Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone

Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone

Biological and chemical studies on aryl hydrocarbon receptor induction by the p53 inhibitor pifithrin-α and its condensation product pifithrin-β

THE OLIVACINE DERIVATIVE S 16020 (9-HYDROXY-5,6-DIMETHYL-N-[2-(DIMETHYLAMINO)ETHYL)-6H-PYRIDO(4,3-B)-CARBAZOLE-1-CARBOXAMIDE) INDUCES CYP1A AND ITS OWN METABOLISM IN HUMAN HEPATOCYTES IN PRIMARY CULTURE

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