Journal Article

Involvement of p38 MAPK and Nrf2 in phenolic acid-induced P-form phenol sulfotransferase expression in human hepatoma HepG<sub>2</sub> cells

Chi-Tai Yeh and Gow-Chin Yen

in Carcinogenesis

Volume 27, issue 5, pages 1008-1017
Published in print May 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI:
Involvement of p38 MAPK and Nrf2 in phenolic acid-induced P-form phenol sulfotransferase expression in human hepatoma HepG2 cells

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Phenolic acids have significant biological and pharmacological properties and some have demonstrated remarkable ability to alter sulfate conjugation. However, the modulation mechanisms of phenolic acids on phenol sulfotransferase expression have not been described. In the present study, we investigated the effects of phenolic acids on the expression of the Phase II P-form of phenol sulfotransferase (PST-P) in human hepatoma HepG2 cells. RT–PCR and western blot data revealed that gallic acid induced increase in PST-P expression at the mRNA and protein levels, respectively. This induction was also marked by an increase in PST-P activity. Actinomycin D and cycloheximide inhibited gallic acid-responsive PST-P mRNA expression, indicating that gallic acid is a requirement for transcription and de novo protein synthesis. Transient transfection of HepG2 cells with a reporter plasmid of the upstream region of the human PST gene caused a significant increase in reporter gene activity after gallic acid exposure. Moreover, gallic acid increased the nuclear levels of Nrf2, a transcription factor governing antioxidant response element (ARE). Electrophoretic mobility shift assay showed increased binding of nuclear proteins to ARE consensus sequence after treatment with gallic acid. While investigating the signaling pathways responsible for PST-P induction, we observed that gallic acid activated the p38 mitogen-activated protein kinase (MAPK) pathway. SB203580, a specific inhibitor of p38 MAPK, abolished gallic acid-induced PST-P protein expression. Similarly, gallic acid also caused an accumulation of Nrf2. Moreover, the protective effects of gallic acid on tert-butyl hydroperoxide-induced toxicity was partially blocked by p38 MAPK and PST-P inhibitors, further demonstrating that gallic acid attenuates oxidative stress through a pathway that involves p38 MAPK and PST-P. These results indicate that gallic acid is a potent inducer of PST-P and that PST-P induction is responsible for the gallic acid-mediated cytoprotection against oxidative damage.

Keywords: ARE, antioxidant responsive element; AhR, aryl hydrocarbon receptor; t-BHQ, tert-Butyl hydroquinone; t-BHP, tert-Butyl hydroperoxide; DCNP, 2; 4-Dichloro- 6-nitrophenol; ERK, extracellualr signal-regulated protein kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GST, glutathione S-transfersase; JNK, c-Jun N-terminal kinase; Keap 1, Kelch-like ECH-associated protein-1; MTT, 3-(4,5-Dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide; MAPK, mitogen-activated protein kinase; NQO-1, NAD(P)H: quinine oxidoreductase 1; Nrf2, nuclear factor-E2-related factor-2; ORACROO, oxygen radical absorbance capacity; PST-P, P-form phenosulfotransferases; RT–PCR, reverse transcriptase–polymerase chain rection; SDS–PAGE, sodium dodecyl sulfate–polyacrylamide gels; TEAC, trolox equivalent antioxidant capacity; TBST, Tris-buffered saline Tween-20; XRE, xenobiotics responsive element

Journal Article.  8868 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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