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Title: Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: Comparison with arsenite

Abstract

Previous work in our laboratory has shown that acute exposure of primary rat hepatocyte cultures to non-toxic concentrations of arsenite causes major decreases in the DEX-mediated induction of CYP3A23 protein, with minor decreases in CYP3A23 mRNA. To elucidate the mechanism for these effects of arsenite, the effects of arsenite and proteasome inhibition, separately and in combination, on induction of CYP3A23 protein were compared. The proteasome inhibitor, MG132, inhibited proteasome activity, but also decreased CYP3A23 mRNA and protein. Lactacystin, another proteasome inhibitor, decreased CYP3A23 protein without affecting CYP3A23 mRNA at a concentration that effectively inhibited proteasome activity. This result, suggesting that the action of lactacystin is similar to arsenite and was post-transcriptional, was confirmed by the finding that lactacystin decreased association of DEX-induced CYP3A23 mRNA with polyribosomes. Both MG132 and lactacystin inhibited total protein synthesis, but did not affect MTT reduction. Arsenite had no effect on ubiquitination of proteins, nor did arsenite significantly affect proteasomal activity. These results suggest that arsenite and lactacystin act by similar mechanisms to inhibit translation of CYP3A23.

Authors:
 [1];  [2];  [2];  [1];  [2];  [2];  [1];  [2];  [3];  [1];  [2];  [2];  [4]
  1. Veterans Administration Medical Center, White River Junction, VT 05009 (United States)
  2. (United States)
  3. Lilly Research Laboratories, Indianapolis, IN 46285 (United States)
  4. Veterans Administration Medical Center, White River Junction, VT 05009 (United States) and Department of Microbiology/Immunology, Dartmouth College, Hanover, NH 03755 (United States) and Department of Medicine, Dartmouth College, Hanover, NH 03755 (United States). E-mail: ralph.c.nichols@dartmouth.edu
Publication Date:
OSTI Identifier:
20850498
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2006.09.007; PII: S0041-008X(06)00318-8; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACUTE EXPOSURE; ARSENIC; BIOSYNTHESIS; BROMIDES; DEXAMETHASONE; HYDROXYLATION; INHIBITION; LIVER CELLS; NITROPHENOL; PROTEINS; RATS; TOXICITY

Citation Formats

Noreault-Conti, Trisha L., Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755, Vermont Forensic Laboratory, Waterbury, VT 05671, Jacobs, Judith M., Department of Microbiology/Immunology, Dartmouth College, Hanover, NH 03755, Department of Biochemistry, Dartmouth College, Hanover, NH 03755, Trask, Heidi W., Department of Biochemistry, Dartmouth College, Hanover, NH 03755, Wrighton, Steven A., Sinclair, Jacqueline F., Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755, Department of Biochemistry, Dartmouth College, Hanover, NH 03755, and Nichols, Ralph C. Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: Comparison with arsenite. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.09.007.
Noreault-Conti, Trisha L., Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755, Vermont Forensic Laboratory, Waterbury, VT 05671, Jacobs, Judith M., Department of Microbiology/Immunology, Dartmouth College, Hanover, NH 03755, Department of Biochemistry, Dartmouth College, Hanover, NH 03755, Trask, Heidi W., Department of Biochemistry, Dartmouth College, Hanover, NH 03755, Wrighton, Steven A., Sinclair, Jacqueline F., Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755, Department of Biochemistry, Dartmouth College, Hanover, NH 03755, & Nichols, Ralph C. Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: Comparison with arsenite. United States. doi:10.1016/j.taap.2006.09.007.
Noreault-Conti, Trisha L., Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755, Vermont Forensic Laboratory, Waterbury, VT 05671, Jacobs, Judith M., Department of Microbiology/Immunology, Dartmouth College, Hanover, NH 03755, Department of Biochemistry, Dartmouth College, Hanover, NH 03755, Trask, Heidi W., Department of Biochemistry, Dartmouth College, Hanover, NH 03755, Wrighton, Steven A., Sinclair, Jacqueline F., Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755, Department of Biochemistry, Dartmouth College, Hanover, NH 03755, and Nichols, Ralph C. Fri . "Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: Comparison with arsenite". United States. doi:10.1016/j.taap.2006.09.007.
@article{osti_20850498,
title = {Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: Comparison with arsenite},
author = {Noreault-Conti, Trisha L. and Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755 and Vermont Forensic Laboratory, Waterbury, VT 05671 and Jacobs, Judith M. and Department of Microbiology/Immunology, Dartmouth College, Hanover, NH 03755 and Department of Biochemistry, Dartmouth College, Hanover, NH 03755 and Trask, Heidi W. and Department of Biochemistry, Dartmouth College, Hanover, NH 03755 and Wrighton, Steven A. and Sinclair, Jacqueline F. and Department of Pharmacology/Toxicology, Dartmouth College, Hanover, NH 03755 and Department of Biochemistry, Dartmouth College, Hanover, NH 03755 and Nichols, Ralph C.},
abstractNote = {Previous work in our laboratory has shown that acute exposure of primary rat hepatocyte cultures to non-toxic concentrations of arsenite causes major decreases in the DEX-mediated induction of CYP3A23 protein, with minor decreases in CYP3A23 mRNA. To elucidate the mechanism for these effects of arsenite, the effects of arsenite and proteasome inhibition, separately and in combination, on induction of CYP3A23 protein were compared. The proteasome inhibitor, MG132, inhibited proteasome activity, but also decreased CYP3A23 mRNA and protein. Lactacystin, another proteasome inhibitor, decreased CYP3A23 protein without affecting CYP3A23 mRNA at a concentration that effectively inhibited proteasome activity. This result, suggesting that the action of lactacystin is similar to arsenite and was post-transcriptional, was confirmed by the finding that lactacystin decreased association of DEX-induced CYP3A23 mRNA with polyribosomes. Both MG132 and lactacystin inhibited total protein synthesis, but did not affect MTT reduction. Arsenite had no effect on ubiquitination of proteins, nor did arsenite significantly affect proteasomal activity. These results suggest that arsenite and lactacystin act by similar mechanisms to inhibit translation of CYP3A23.},
doi = {10.1016/j.taap.2006.09.007},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}