Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes.

Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Research Abstract Details 

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Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Abstract Text:

Parikshit C Das,Yan Cao,Nathan Cherrington,Ernest Hodgson,Randy L Rose,

Recent studies have demonstrated the potential of pesticides to either inhibit or induce xenobiotic metabolizing enzymes in humans. Exposure of human hepatocytes to doses of fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl) sulfinyl]-1H-pyrazole-3-carbonitrile) ranging from 0.1 to 25 microM resulted in a dose dependent increase in CYP1A1 mRNA expression (3.5 to approximately 55-fold) as measured by the branched DNA assay. In a similar manner, CYP3A4 mRNA expression was also induced (10-30-fold), although at the higher doses induction returned to near control levels. CYP2B6 and 3A5 were also induced by fipronil, although at lower levels (2-3-fold). Confirmation of bDNA results were sought through western blotting and/or enzyme activity assays. Western blots using CYP3A4 antibody demonstrated a dose responsive increase from 0.5 to 1 microM followed by decreasing responses at higher concentrations. Similar increases and decreases were observed in CYP3A4-specific activity levels as measured using 6beta-hydroxytestosterone formation following incubation with testosterone. Likewise, activity levels for a CYP1A1-specific substrate, luciferin CEE, demonstrated that CYP1A1 enzyme activities were maximally induced by 1 microM fipronil followed by dramatically declining activity measurements at 10 and 25 microM. Cytotoxic effects of fipronil and fipronil sulfone were examined using the adenylate kinase and the trypan blue exclusion assays in HepG2 cells and human hepatocytes. The results indicate both that HepG2 cells and primary human hepatocytes are sensitive to the cytotoxic effects of fipronil. The maximum induction of adenylate kinase was ca. 3-fold greater than the respective controls in HepG2 and 6-10-fold in the case of primary hepatocytes. A significant time- and dose-dependent induction of adenylate kinase activity in HepG2 cells was noted from 0.1 to 12.5 microM fipronil followed by decreasing activities at 25 and 50 microM. For fipronil sulfone, cytotoxic effects increased throughout the dose range. The trypan blue assay indicated that cytotoxic effects contributing to an increase of greater than 10% of control values was indicated at doses above 12.5 microM. However, fipronil sulfone induced cytotoxic effects at lower doses. The possibility that cytotoxic effects were due to apoptosis was indicated by significant time- and dose-dependent induction of caspase-3/7 activity in both HepG2 cells and human hepatocytes. Fipronil mediated activation of caspase-3/7 in concurrence with compromised ATP production and viability are attributed to apoptotic cell death.

Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Publishing Authors By Initials

PC Das,Y Cao,N Cherrington,E Hodgson,RL Rose,

For similar genetic processes: gene expression: transcription, genetic research abstracts see: genetic processes: gene expression: transcription, genetic research

PUBMED ID PMID:

MEDLINE DATE:

Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Chemico-biological interactions

VOLUME: 164

Page Numbers: 200-14

Journal Abbreviation: Chem. Biol. Interact.

ISSN: 0009-2797

DAY: 6

MONTH: 10

YEAR: 2006

Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 227276

Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Keywords Mesh Terms:

KEYWORDS: Transcription, Genetic

MESH TERMS: genetics

Chemical & Substance for Abstract: Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes. Information

Substance Name: Caspase 7

Registry Number: EC 3.4.22.-

Grant and Affiliation Information for Fipronil induces CYP isoforms and cytotoxicity in human hepatocytes.

AFFILIATION: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA.

Country: Ireland

AGENCY: United States NIOSH

GRANT: OH07551-ECU

ACRONYM: OH

MEDLINETA: Chem Biol Interact

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