Characterization of the Ah receptor mediating aryl hydrocarbon hydroxylase induction in the human liver cell line Hep G2

Roberts, Eve A.; Johnson, Kathene C.; Harper, Patricia A.; Okey, Allan B.

doi:10.1016/0003-9861(90)90743-i

Cited by 64 publications

(20 citation statements)

References 40 publications

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“…UGT1A1 was responsive to chrysin and 3-MC in a PXR-independent manner. Although the expression of some nuclear receptors such as PXR and CAR is nonexistent or subdued in HepG2 cells, the AhR is endogenously expressed in these cells (Roberts et al, 1990;Lemaire et al, 2004;Rencurel et al, 2005). These results suggested that chrysin regulation is AhR-mediated because a functional AhRE is present in the UGT1A1 promoter, whereas it is not in the CYP2B6 promoter (Fig.…”

Section: Discussionmentioning

confidence: 92%

Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

Smith¹,

Graham²,

Król³

et al. 2005

J Pharmacol Exp Ther

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Chrysin, a dietary flavonoid, has been shown to markedly induce UGT1A1 expression and activity in HepG2 and Caco-2 cell lines; thus, it has been suggested to have clinical utility in the treatment of UGT1A1-mediated deficiencies, such as unconjugated hyperbilirubinemia or the prevention of 7-ethyl-10-hydroxycamptothecin (SN-38) toxicity. However, little is known about its induction potential in a more physiologically relevant model system, such as primary hepatocyte culture. In this study, induction of UGT1A1 expression (mRNA, protein, and activity) was investigated in primary human hepatocyte cultures after treatment with chrysin and other prototypical inducers. Endogenous nuclear receptor-mediated UGT1A1 induction was studied using transient transfection reporter assays in primary human hepatocytes and HepG2 cells. Results indicated that induction of UGT1A1 expression was minimal in human hepatocytes treated with chrysin compared with that in HepG2 cells (1.2-versus 11-fold, respectively). Subsequent experiments to determine whether the differential response was due to its metabolic stability revealed strikingly different elimination rate constants between the two cell systems (half-life of 13 min in human hepatocytes versus 122 min in HepG2 cell suspensions). Further study demonstrated that UGT1A1 mRNA expression could be induced in human hepatocyte cultures by either increasing the chrysin dosing frequency or by modulating chrysin metabolism, suggesting that the differential induction observed in hepatocytes and HepG2 cells was due to differences in the metabolic clearance of chrysin. In conclusion, this study suggests that the metabolic stability of chrysin likely would limit its ability to induce UGT1A1 in vivo.

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Section: Discussionmentioning

confidence: 92%

Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

Smith¹,

Graham²,

Król³

et al. 2005

J Pharmacol Exp Ther

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“…Synthesis of serum proteins and cell surface receptor-mediated functions such as lipoprotein uptake (which probably plays a role in the uptake of PCDDs; Shireman and Wei 1987) are closely similar to those in normal hepatocytes (Knowles et al 1980;Havekes et al 1983). However, species differences in dioxin receptor properties have also been noted (Roberts et al 1990;Poland et al 1990). …”

Section: Introductionmentioning

confidence: 92%

“…HepG2 cells have proven to represent a suitable human cell model. They contain the human receptor controlling the induction of P4501AI (Cresteil et al 1987;Grant et al 1988;Labruzzo et al 1989;Roberts et al 1990). Synthesis of serum proteins and cell surface receptor-mediated functions such as lipoprotein uptake (which probably plays a role in the uptake of PCDDs; Shireman and Wei 1987) are closely similar to those in normal hepatocytes (Knowles et al 1980;Havekes et al 1983).…”

Section: Introductionmentioning

confidence: 99%

Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their constituents in human HepG2 cells

et al. 1992

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Dose-response curves of the induction of P4501A1-dependent 7-ethoxyresorufin O-deethylase (EROD) were analyzed in human hepatoma HepG2 cells treated with defined mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their 2,3,7,8-substituted constituents, similar to previous studies with rat hepatocytes and H4IIE cells (Schrenk et al. 1991). PCDDs appear to act less potent in human HepG2 cells in comparison with rat cells. For example, EC50 values of 2,3,7,8-Cl4DD were 8-fold and 19-fold higher than in rat H4IIE cells and hepatocytes, respectively. EC50 values of PCDDs were compared with that of 2,3,7,8-Cl4DD and expressed as 2,3,7,8-Cl4DD equivalents (TEs). Although the rank order of PCDD potencies was similar, TEs for some PCDDs (1,2,3,7,8-Cl5DD; TE = 0.75 and 1,2,3,7,8-Cl6DD; TE = 0.61) were found to be higher than in the rat system. In contrast to rat cells no significant induction of EROD could be detected with Cl8DD in HepG2 cells up to its limit of solubility. Experimentally determined TEs of PCDD mixtures containing 49 constituents were found to be largely due to additive effects of their 2,3,7,8-substituted constituents.

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“…Molybdate is particularly necessary for stabilizing the human AHR and the low affinity mouse (Ah d ) AHR so they it may be characterized in binding studies (Manchester et al, 1987) (Golas et al, 1990;Okey et aI., 1989;Roberts et al, 1990). In contrast, molybdate contributes to destabilization of the rat AHR (Kester & Gasiewicz, 1987).…”

Section: Development Of a Competitive Binding Assay For In Vitro-exprmentioning

confidence: 99%

Characterization of an aryl hydrocarbon receptor from a cetacean : an approach for assessing contaminant susceptibility in protected species

Jensen¹

2000

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Characterization of the Ah receptor mediating aryl hydrocarbon hydroxylase induction in the human liver cell line Hep G2

Cited by 64 publications

References 40 publications

Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their constituents in human HepG2 cells

Characterization of an aryl hydrocarbon receptor from a cetacean : an approach for assessing contaminant susceptibility in protected species

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