Journal Article

Modulation of Aflatoxin B1–Mediated Genotoxicity in Primary Cultures of Human Hepatocytes by Diindolylmethane, Curcumin, and Xanthohumols

Kerstin Gross-Steinmeyer, Patricia L. Stapleton, Julia H. Tracy, Theo K. Bammler, Stephen C. Strom, Donald R. Buhler and David L. Eaton

in Toxicological Sciences

Volume 112, issue 2, pages 303-310
Published in print December 2009 | ISSN: 1096-6080
Published online September 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp206
Modulation of Aflatoxin B1–Mediated Genotoxicity in Primary Cultures of Human Hepatocytes by Diindolylmethane, Curcumin, and Xanthohumols

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This study employed cultured human primary hepatocytes to investigate the ability of the putative chemopreventive phytochemicals curcumin (CUR), 3,3′-diindolylmethane (DIM), isoxanthohumol (IXN), or 8-prenylnaringenin (8PN) to reduce DNA adduct formation of the hepatocarcinogen aflatoxin B1 (AFB). Following 48 h of pretreatment, DIM and 8PN significantly increased AFB-DNA adduct levels, whereas CUR and IXN had no effect. DIM greatly enhanced the transcriptional expression of cytochrome P450 (CYP) 1A1 and CYP1A2 mRNA. Glutathione S-transferase mRNAs were not increased by any of the treatments. In vitro enzyme activity assays demonstrated that 8PN and DIM, but not CUR or IXN, inhibited human CYP1A1, CYP1A2, and CYP3A4 activities. To distinguish between treatment effects on transcription versus direct effects on enzyme activity for DIM, we evaluated the effects of pretreatment alone (transcriptional activation) versus cotreatment alone (enzyme inhibition). The results demonstrated that effects on gene expression, but not catalytic activity, are responsible for the observed effects of DIM on AFB-DNA adduct formation. The increase in AFB-DNA damage following DIM treatment may be explained through its substantial induction of CYP1A2 and/or its downregulation of GSTM1, both of which were significant. The increase in DNA damage by DIM raises potential safety risks for dietary supplements of DIM and its precursor indole-3-carbinol.

Keywords: phytochemicals; biotransformation; hepatocytes; human; CYP

Journal Article.  5781 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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