Implication of the "4S" polycyclic aromatic hydrocarbon binding protein in the transregulation of rat cytochrome P-450c expression

Houser, William H.; Hines, Ronald N.; Bresnick, Edward

doi:10.1021/bi00347a050

Cited by 43 publications

(10 citation statements)

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“…Previously, B[e]P had been demonstrated to be a selective ligand for the 4 S PAH-binding protein (17)(18)(19)(20)(21)(22)(23). In the present study, we have shown that this PAH is also able to induce the expression of CYP1A1 in the GNMT-transfected CHO cells, whereas TCDD, a prototypic ligand for the Ah receptor, failed to do so.…”

Section: Discussionsupporting

confidence: 47%

“…Evidence has been published suggesting that the induction of rat CYP1A1 after treatment with PAHs, such as B[a]P or B[e]P, may require an Ah receptor-independent pathway mediated by another cytosolic receptor protein, the 4 S PAHbinding protein (17)(18)(19)(20)(21)(22)(23). Both the Ah receptor and 4 S PAHbinding protein exhibit distinct ligand binding specificities, with 3-methylcholanthrene interacting with both.…”

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confidence: 99%

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Glycine N-Methyltransferase Is an Example of Functional Diversity

Bhat

Bresnick

1997

Journal of Biological Chemistry

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Polycyclic aromatic hydrocarbons such as B[a]P 1 , 3-methylcholanthrene, and TCDD are environmental pollutants that elicit a variety of toxic, teratogenic, and carcinogenic responses in exposed animals (1-7). In addition, these substances are potent inducers of certain biotransformation reactions that are catalyzed by the cytochrome P-450-dependent monooxygenases, a super family of isozymic hemoproteins comprising more than 12 gene groups (8). These isozymes display broad substrate specificity and metabolize both endogenous substrates and xenobiotics to electrophilic derivatives, some of which can interact with DNA, thereby potentially activating protooncogenes or inactivating tumor suppressor genes.A principal cytochrome P-450 induced by B[a]P, 3-methylcholanthrene, or TCDD is CYP1A1, which is in part responsible for the activation of PAHs to carcinogenic intermediates. This induction is mediated by receptors, such as the Ah receptor (or dioxin receptor, 8 S protein). The Ah receptor-mediated mechanism is the best characterized and most widely accepted model for PAH-induced expression of CYP1A1 (9, 10). Upon ligand binding, the Ah receptor undergoes a temperature-dependent transformation accompanied by translocation into the nucleus where the ligand receptor complex binds to specific cis-elements (also known as XREs and DREs) present in the 5Ј-regulatory regions of CYP1A1 and of several other genes in the Ah gene battery. The result of such interaction is the transcriptional activation of Ah responsive genes (3,5,6,11). The Ah receptor contains a 95-kDa helix-loop-helix motif, characteristic of several transcriptional activators (12, 13). The mechanism as outlined is more complicated because functional Ah receptor represents a heterodimer that contains, in addition to the ligand binding moiety, a second helix-loop-helix 84-kDa protein component, known as ARNT, which is needed for the nuclear translocation of the ligand-receptor complex (14 -16). In addition, heat shock protein 90 plays an important role in the intracellular localization of the Ah receptor (see review in Ref. 42).Evidence has been published suggesting that the induction of rat CYP1A1 after treatment with PAHs, such as B[a]P or B[e]P, may require an Ah receptor-independent pathway mediated by another cytosolic receptor protein, the 4 S PAHbinding protein (17)(18)(19)(20)(21)(22)(23). Both the Ah receptor and 4 S PAHbinding protein exhibit distinct ligand binding specificities, with 3-methylcholanthrene interacting with both. B[a]P and B[e]P have been demonstrated to act solely as ligands for the 4 S protein in rat liver and rat hepatoma cells (17, 24 -28). Like the Ah receptor, the 4 S protein undergoes nuclear translocation upon interaction with the PAH (17, 29 -31) and complexes to cis-response elements in different regulatory regions of CYP1A1 (21,32,33).The 4 S protein has been purified to homogeneity using a * This research was supported by National Institutes of Health Grant CA 36105. The costs of publication of this article were defrayed i...

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Section: Discussionsupporting

confidence: 47%

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confidence: 99%

Glycine N-Methyltransferase Is an Example of Functional Diversity

Bhat

Bresnick

1997

Journal of Biological Chemistry

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“…Recently, a benzo[a]pyrene-binding protein was purified from rat hepatic cytosol [6]; the complex was able to bind total rat liver DNA as well as subclones containing portions of the rat cytochrome P-450c gene, implicating this 4-S protein in the transregulation of its expression. The present report provides additional information on the binding capacities of the 4-S protein.…”

Section: Discussionmentioning

confidence: 99%

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

Roy

Fernández

Lesca

1988

European Journal of Biochemistry

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The binding characteristics of 4-S components (carcinogen-binding protein) from livers of Sprague-Dawley rats, C57BL/6 and DBA/2 mice have been examined before and after separation from other binding components presents in the cytosol. Competitive potency of 3-methylcholanthrene, benzo[a]pyrene, P-naphthoflavone and 20 ellipticines, a series of compounds differently substituted on the dimethyl-pyrido-carbazole nucleus and deprived of carcinogenic activity, has been determined with [3H]3-methylcholanthrene and/or [3H]benzo[a]pyrene as radioligands. The inducing ability of the same compounds for aryl hydrocarbon hydroxylase and for ethoxyresorufin-0-deethylase has been compared to their affinity for the 4-S protein and the Ah receptor respectively. The main results of this study are as follows.1. The intrinsic binding characteristics of 4-S proteins were dependent on both the nature of the radioligand used and the presence or absence of other cytosolic binding components.2. The heterocyclic ellipticines were revealed as strong ligands for the carcinogen-binding protein (stronger than benzo[a]pyrene for five derivatives substit'uted in the A ring of ellipticine), with IC50 values ranging from 0.047 pM (8-hydroxyellipticine) to 5.8 pM (Nz-ethyl-9-hydroxyellipticinium).3. When the affinity of ellipticines was plotted versus their inducing ability of aryl hydrocarbon hydroxylase and ethoxyresorufin-0-deethylase, it appears that a good correlation exists for the Ah receptor but not for the 4-S protein.It is concluded that these data, as well as the lack of enzymatic induction after benzo[a]pyrene treatment of DBA/2 mice, which display a high level of 4-S protein, do not support the implication of this binding component in the positive control of cytochrome P-450 induction.

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“…The differences in timecourse may be due to differences in the half-lives of the relevant mRNAs andor proteins (Hargrove and Schmidt, 1989), and it is clear that parallel dose-response curves for different biological responses can be separated by as much as several orders of magnitude and still be mediated by the same receptor (Okey et al, 1995). It is important to point out that a rat liver cytosolic 4 S carcinogen-binding protein may also be involved in the transcriptional induction of CYPl A I expression in response to nonhalogenated aromatic hydrocarbons (Houser et al, 1985 LeBlanc and Waxrnan, 1990) and cytokines and inflammatory mediators (Morgan, 1989;Morgan. 1993;Chen et al, 1995b) being the best characterized negative regulators.…”

Section: Correlation Analysismentioning

confidence: 99%