Journal Article

Benzo[a]pyrene Increases the Nrf2 Content by Downregulating the <i>Keap1</i> Message

Phuong Minh Nguyen, Miki Susanto Park, Marilynn Chow, Jae H. Chang, Lisa Wrischnik and William K. Chan

in Toxicological Sciences

Volume 116, issue 2, pages 549-561
Published in print August 2010 | ISSN: 1096-6080
Published online May 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq150
Benzo[a]pyrene Increases the Nrf2 Content by Downregulating the Keap1 Message

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We employed the suppressive subtractive hybridization to identify 41 up- and downregulated transcripts in Jurkat cells after benzo[a]pyrene (BaP) treatment. Among the 21 downregulated transcripts, we found that BaP suppresses the Keap1 transcript by 7.5-fold. Subsequent analyses revealed that BaP significantly suppresses the Keap1 message and protein levels to about 40 and 60%, respectively, of the vehicle controls in Jurkat cells without reactive oxygen species involvement. In addition, the nuclear Nrf2 (nuclear factor erythroid 2-related factor) protein content is significantly increased by 2.6-fold. The same BaP treatment to Hepa1c1c7 cells also downregulates the Keap1 message and protein levels to a similar extent. When we treated Jurkat cells with 3-(4-morpholinyl)propyl isothiocyanate, which is known to increase the amount of the Nrf2 content, we found that there is no change in the Keap1 message, but the amount of the Keap1 (kelch-like ECH-associated protein 1) protein is reduced to 75% of the vehicle controls. Although both Nrf2 target messages nqo1 and gstp1 are upregulated by BaP in Jurkat cells, only GSTP1 is upregulated at the protein level. Unlike Hepa1c1c7 cells, Jurkat cells have no detectable aryl hydrocarbon receptor and BaP metabolites, minimal CYP1A1 activity, and no quinone oxidoreductase 1 (NQO1) activity. We concluded that BaP, but not its metabolites, increases the amount of the nuclear Nrf2 protein by downregulating the Keap1 message in Jurkat cells.

Keywords: benzo[a]pyrene; gene regulation; suppressive subtractive hybridization; Keap1; Nrf2

Journal Article.  8314 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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