Role of the aromatic hydrocarbon receptor in the suppression of cytochrome P-450 2C11 by polycyclic aromatic hydrocarbons

Safa, Behnam; Lee, Chunja; Riddick, David S.

doi:10.1016/s0378-4274(96)03843-x

Cited by 25 publications

(22 citation statements)

References 78 publications

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“…CYP2C11 is the most abundant constitutive hepatic P450 in male rats and a primary physiological regulator of its expression is the pulsatile pattern of pituitary growth hormone (GH) secretion, with signal transducer and activator of transcription 5b (STAT5b) as an intracellular messenger at least partially responsible for the sexually dimorphic expression (Park and Waxman 2001;Ahluwalia et al 2004;Clodfelter et al 2006). Aromatic hydrocarbons cause CYP2C11 down-regulation via a transcriptional mechanism in male rats in vivo (Jones and Riddick 1996;Lee and Riddick 2000) and in cultured primary rat hepatocytes (Safa et al 1997;Bhathena et al 2002). AHR involvement in this suppression response was suggested by structure-activity relationship data (Safa et al 1997) and we showed that the activated AHR binds to a putative dioxin-responsive element (DRE) in the CYP2C11 5′-flanking region (Bhathena et al 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Aromatic hydrocarbons cause CYP2C11 down-regulation via a transcriptional mechanism in male rats in vivo (Jones and Riddick 1996;Lee and Riddick 2000) and in cultured primary rat hepatocytes (Safa et al 1997;Bhathena et al 2002). AHR involvement in this suppression response was suggested by structure-activity relationship data (Safa et al 1997) and we showed that the activated AHR binds to a putative dioxin-responsive element (DRE) in the CYP2C11 5′-flanking region (Bhathena et al 2002). MC treatment causes down-regulation of luciferase reporter constructs driven by the CYP2C11 promoter and 5′-flanking region when delivered to the liver of living male rats via high-volume tail vein injection (Sawaya and Riddick 2008b), but no suppression of these reporter plasmids in response to MC or TCDD is observed in transfected continuous cell lines or primary rat hepatocytes (Bhathena et al 2002;Sawaya and Riddick 2008a).…”

Section: Introductionmentioning

confidence: 99%

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Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Lee

Riddick

2012

Can. J. Physiol. Pharmacol.

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The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands and mediates adaptive and toxic responses to the environmental pollutant, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially non-metabolized AHR agonist and Ahr −/− mice as the preferred model to determine the AHR-dependence of biological responses, we now show that two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHRdependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes. Keywordsaryl hydrocarbon receptor; 2,3,7,8-tetrachlorodibenzo-p-dioxin; cytochrome P450; growth hormone receptor; Janus kinase 2; signal transducer and activator of transcription 5b; cytokineinducible Src homology 2 domain-containing protein; major urinary protein 2; inflammatory markers; NADPH-cytochrome P450 oxidoreductase

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Lee

Riddick

2012

Can. J. Physiol. Pharmacol.

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“…Expression of CYP2C11, the predominant constitutive hepatic P450 in male rats, is down-regulated by aromatic hydrocarbons via a transcriptional mechanism both in vivo (Jones and Riddick, 1996;Lee and Riddick, 2000) and in cultured primary rat hepatocytes (Safa et al, 1997;Bhathena et al, 2002). Although the AHR seems to be involved in this response (Safa et al, 1997) and 2,3,7,8-tetrachlorodibenzo-p-dioxin-activated AHR binds to a putative dioxin-responsive element (DRE) in the CYP2C11 5Ј-flanking region (Bhathena et al, 2002), use of in vitro DNase footprinting and luciferase reporter assays has not yet elucidated the definitive molecular mechanism involved.…”

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confidence: 99%

Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene

Lee¹,

Hutson²,

Tzau³

et al. 2006

Drug Metab Dispos

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ABSTRACT:3-Methylcholanthrene (MC) activates the aryl hydrocarbon receptor and increases expression of cytochrome P450 (P450) enzymes such as CYP1A1. MC also decreases expression of CYP2C11, the major hepatic P450 in male rats that is regulated by pulsatile growth hormone (GH) secretion via a pathway partially dependent on signal transducer and activator of transcription 5b (STAT5b). If disruption of this GH signaling pathway is important for MC's ability to suppress CYP2C11 transcription, we hypothesize that MC suppresses other male-specific genes (e.g., mouse Cyp2d9) regulated by pulsatile GH with STAT5b dependence. We examined the time course of MC's effects on hepatic P450s and GH signaling components in male C57BL/6 mice. P450 content, heme content, and NADPH P450 oxidoreductase activity were induced 2.3-, 1.8-, and 1.3-fold, respectively, by MC. MC dramatically induced CYP1A1 mRNA, protein, and catalytic activity. MC caused a 42% decrease in CYP2D9 protein, a 28% decrease in CYP2D9 mRNA, and a 27% decrease in testosterone 16␣-hydroxylation activity. MC caused a pronounced decrease in CYP3A protein; however, there was no apparent change in testosterone 6␤-hydroxylation activity, and changes in mRNA levels for CYP3A forms were relatively small. Expression of GH receptor and major urinary protein 2, a gene regulated by GH with STAT5b dependence, was decreased by MC at the mRNA level. These results show that MC suppresses mouse Cyp2d9, a pulsatile GH-and STAT5b-dependent male-specific gene, via a pretranslational mechanism that may involve disrupted GH signaling. Mouse CYP3A protein levels are dramatically decreased by MC via a mechanism that is not yet understood.

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“…We are particularly interested in determining whether the AHR mediates this negative transcriptional response. Our structure-activity relationship study with a series of anthracene derivatives showed that affinity for binding to the AHR and the potency for transforming the AHR to its DNA-binding form correlated with the ability of these compounds to down-regulate CYP2C11 protein expression in primary rat hepatocytes cultured on Matrigel (BD Biosciences, Bedford, MA) (Safa et al, 1997). In the same hepatocyte system, TCDD decreased the level of CYP2C11 mRNA without altering the half-life of the message, providing additional support for an effect on transcription (Bhathena et al, 2002).…”

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confidence: 99%

Transcriptional Suppression of Cytochrome P450 Genes by Endogenous and Exogenous Chemicals

Riddick¹,

Lee²,

Bhathena³

et al. 2004

Drug Metab Dispos

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Role of the aromatic hydrocarbon receptor in the suppression of cytochrome P-450 2C11 by polycyclic aromatic hydrocarbons

Cited by 25 publications

References 78 publications

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene

Transcriptional Suppression of Cytochrome P450 Genes by Endogenous and Exogenous Chemicals

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