TY - JOUR
T1 - Effects of suberoylanilide hydroxamic acid and trichostatin A on induction of cytochrome P450 enzymes and benzo[a]pyrene DNA adduct formation in human cells
AU - Hooven, Louisa A.
AU - Mahadevan, Brinda
AU - Keshava, Channa
AU - Johns, Christopher
AU - Pereira, Cliff
AU - Desai, Dhimant
AU - Amin, Shantu
AU - Weston, Ainsley
AU - Baird, William M.
N1 - Funding Information:
This study was supported in part by grant CA28825 from the National Cancer Institute, DHHS. Statistical analysis was provided by the Statistics Core Facility of the Environmental Health Sciences Center at Oregon State University, and the Cell Culture Core of the same center provided support for the cell culture work reported in this study. These core facilities were made possible in part by grant number P30 ES00210 from the National Institute of Environmental Health Sciences, NIH. Our gratitude goes to Tamara Musafia, who has offered technical advice and assistance as well as editorial suggestions. The authors would also like to acknowledge the assistance of Arta Pecaj, Jennifer Atkin and Eric Brooks.
PY - 2005/3/1
Y1 - 2005/3/1
N2 - In this study, we investigated the effects of histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) on the metabolism of polycyclic aromatic hydrocarbons (PAH) in human mammary carcinoma derived MCF-7 cells in culture. Benzo[a]pyrene (B[a]P) induces cytochrome P450 (CYP) 1A1, CYP1B1 and other xenobiotic metabolizing enzymes. Results from our study indicated a significant increase in CYP activity in comparison to vehicle control in cells treated with SAHA or TSA as measured by ethoxyresorufin-O-deethylase assay. However, co-treatment with 1.0 μM SAHA and BP, reduced the mRNA levels of CYP1B1 relative to B[a]P alone. When co-treated with 1.0 μM TSA and BP, a reduction in the mRNA levels of both CYP1A1 and CYP1B1 was observed relative to BP alone. We further investigated to ascertain if the differential expression and activity of CYP1A1 and CYP1B1 influenced levels of B[a]P DNA adduct formation. MCF-7 cells co-treated with B[a]P and SAHA or TSA formed DNA adducts, although no significant differences in levels of DNA binding were revealed. These results suggest that while CYP enzyme activity and gene expression were affected by the HDAC inhibitors SAHA and TSA, they had no apparent influence on B[a]P DNA binding.
AB - In this study, we investigated the effects of histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) on the metabolism of polycyclic aromatic hydrocarbons (PAH) in human mammary carcinoma derived MCF-7 cells in culture. Benzo[a]pyrene (B[a]P) induces cytochrome P450 (CYP) 1A1, CYP1B1 and other xenobiotic metabolizing enzymes. Results from our study indicated a significant increase in CYP activity in comparison to vehicle control in cells treated with SAHA or TSA as measured by ethoxyresorufin-O-deethylase assay. However, co-treatment with 1.0 μM SAHA and BP, reduced the mRNA levels of CYP1B1 relative to B[a]P alone. When co-treated with 1.0 μM TSA and BP, a reduction in the mRNA levels of both CYP1A1 and CYP1B1 was observed relative to BP alone. We further investigated to ascertain if the differential expression and activity of CYP1A1 and CYP1B1 influenced levels of B[a]P DNA adduct formation. MCF-7 cells co-treated with B[a]P and SAHA or TSA formed DNA adducts, although no significant differences in levels of DNA binding were revealed. These results suggest that while CYP enzyme activity and gene expression were affected by the HDAC inhibitors SAHA and TSA, they had no apparent influence on B[a]P DNA binding.
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U2 - 10.1016/j.bmcl.2005.01.032
DO - 10.1016/j.bmcl.2005.01.032
M3 - Article
C2 - 15713371
AN - SCOPUS:13944280578
SN - 0960-894X
VL - 15
SP - 1283
EP - 1287
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 5
ER -