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Induction of CYP1A1 in primary rat hepatocytes by 3,3',4,4',5-pentachlorobiphenyl: evidence for a switch circuit element.

Authors
French-CT; Hanneman-WH; Chubb-LS; Billings-RE; Andersen-ME
Source
Toxicol Sci 2004 Apr; 78(2):276-286
NIOSHTIC No.
20035337
Abstract
In vivo induction of CYP1A1 in hepatocytes by aryl hydrocarbon receptor agonists is heterogeneous. Using immunohistochemistry, cells appear to be either induced or not induced as if the response of an individual cell is better represented as a switch. We have examined induction of CYP1A1 in vitro in primary rat hepatocytes to distinguish the responses of populations of cells and responses of individual cells. Cells were treated with various concentrations of the aryl hydrocarbon receptor agonist, 3,3',4,4',5-pentachlorobiphenyl. Concentration-response and time-course responses were determined for the population of cells by Western blotting for CYP1A1 protein and by real-time RT-PCR for CYP1A1 mRNA. Individual cell responses were visualized by immunocytochemistry (ICC) for protein and by in situ hybridization (ISH) for mRNA. CYP1A1 mRNA was quantified by frequency distribution analysis of grains observed on the ISH slides. Population responses showed time- and concentration-related increases in induction. Single cell responses appeared as all-or-none in the field, with cells appearing to be induced and others appearing to be not induced. Even at the highest concentrations (2.5 x 10(-7) M), some hepatocytes remained unresponsive. Distribution frequencies of single cell induction were more consistent with a switch with variable levels of induction in cells depending on treatment concentration. Combined with the reports from in vivo studies, our results support a switch with rheostat behavior for individual hepatocytes. Mechanistic studies in liver cell lines that are confirmed to exhibit switch-like induction of single cells will be necessary to assess the molecular pathways of this circuit element.
Keywords
Hepatic-microsomal-enzymes; Hepatitis; Hepatocytes; Hepatotoxicity; Hepatotoxins; Chemical-analysis; Chemical-hypersensitivity; Chemical-indicators; Chemical-properties; Chemical-reactions; Chemical-structure; Chemical-synthesis; Exposure-levels; Exposure-limits; Exposure-methods; Dioxides; Dioxins; Risk-analysis; Risk-factors; Animal-studies; Animals; Cell-alteration; Cell-biology; Cell-cultures; Cell-damage; Cell-division; Cell-function; Cell-metabolism; Cell-migration; Cell-transformation; Cellular-function; Cellular-reactions; Author Keywords: polychlorinated biphenyl; CYP1A1; hepatocytes
Contact
C. T. French, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523
CODEN
TOSCF2
Publication Date
20040401
Document Type
Journal Article
Email Address
Hanneman@colostate.edu
Funding Type
Agriculture; Cooperative Agreement
Fiscal Year
2004
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U50-OH-007545
Issue of Publication
2
ISSN
1096-6080
Source Name
Toxicological Sciences
State
CO
Performing Organization
Colorado State University - Fort Collins
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