Abstract
This article is an invited report of a symposium sponsored by the Division for Drug Metabolism of the American Society for Pharmacology and Experimental Therapeutics held at Experimental Biology 2003 in San Diego, California, April 11-15, 2003. Several members of the cytochrome P450 (P450) superfamily are induced after exposure to a variety of chemical signals, and we have gained considerable mechanistic insight into these processes over the past four decades. In addition, the expression of many P450s is suppressed in response to various endogenous and exogenous chemicals; however, relatively little is known about the molecular mechanisms involved. The goal of this symposium was to critically examine our current understanding of molecular mechanisms involved in transcriptional suppression of CYP genes by endogenous and exogenous chemicals. Specific examples were drawn from the following chemical categories: polycyclic and halogenated aromatic hydrocarbon environmental toxicants, inflammatory mediators, the endogenous sterol dehydroepiandrosterone and peroxisome proliferators, and bile acids. Multiple molecular mechanisms are involved in transcriptional suppression, and these processes often involve rather complex cascades of transcription factors and other regulatory proteins. Mechanistic studies of CYP gene suppression can enhance our understanding of how organisms respond to xenobiotics as well as to perturbations in endogenous chemicals involved in maintaining homeostasis.
Footnotes
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↵1 Abbreviations used are: P450, cytochrome P450; ADIOL, androst-5-ene-3,17-diol; ADIONE, androst-5-ene-3,17-dione; AHR, aromatic hydrocarbon receptor; BARE, bile acid response element; bp, base pair(s); CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; DRE, dioxin-responsive element; FTF, α-fetoprotein transcription factor; FXR, farnesoid X receptor; GH, growth hormone; HCA, hyocholic acid; HDCA, hyodeoxycholic acid; HNF, hepatocyte nuclear factor; IκB, inhibitory protein of nuclear factor-κB; IL, interleukin; JNK, cJun N-terminal kinase; LCA, lithocholic acid; LIP, liver-enriched transcriptional inhibitory protein; LPS, bacterial lipopolysaccharide; LXR, liver X receptor; MAPK, mitogen-activated protein kinase; MC, 3-methylcholanthrene; NF-κB, nuclear factor-κB; PAH, polycyclic aromatic hydrocarbon; PCN, pregnenolone 16α-carbonitrile; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; SHP, small heterodimer partner; STAT, signal transducer and activator of transcription; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TF, transcription factor; VDR, vitamin D receptor.
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Supported in part by Canadian Institutes of Health Research Grant MOP-42399 (D.S.R.), United States Public Health Service Grant DK54774 (R.A.P.), National Research Service Award Fellowship F32 ES05927 (S.L.R.), American Heart Association Predoctoral Fellowship 0110109 (K.K.M.M.), National Institutes of Health Grants DK58379 and DK44442 (J.Y.L.C), and American Heart Association Ohio Valley Affiliates Predoctoral Fellowship and an American Liver Foundation Summer Student Fellowship (A.J.).
- Received October 7, 2003.
- Accepted December 19, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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- Positive and Negative Transcriptional Regulation of Cytochromes P450 by Polycyclic Aromatic Hydrocarbons (D.S.R., C.L., A.B., Y.E.T.)
- Down-Regulation of Cytochromes P450 by Inflammatory Mediators (P.-Y.C., E.T.M.).
- Dehydroepiandrosterone Is Metabolized by and Modulates Expression of Multiple Cytochromes P450 (R.A.P., S.L.R., K.K.M.M.)
- Bile Acid and Nuclear Receptor Regulation of Cytochrome P450 Gene Transcription (A.J., J.Y.L.C.)
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