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Enzyme induction and cytotoxicity in human hepatocytes by chlorpyrifos and N,N-diethyl-m-toluamide (DEET).

Authors
Das-PC; Cao-Y; Roset-RL; Cherringto-N; Hodgson-E
Source
Drug Metabol Drug Interact 2008 Jan; 23(3-4):237-260
NIOSHTIC No.
20036474
Abstract
Xenobiotics, including drugs and environmental chemicals, can influence cytochrome P450 (CYP) levels by altering the transcription of CYP genes. To minimize potential drug-pesticide and pesticide-pesticide interactions it is important to evaluate the potential of pesticides to induce CYP isoforms and to cause cytotoxicity in humans. The present study was designed to examine chlorpyrifos and DEET mediated induction of CYP isoforms and also to characterize their potential cytotoxic effects on primary human hepatocytes. DEET significantly induced CYP3A4, CYP2B6, CYP2A6 and CYP1A2 mRNA expression while chlorpyrifos induced CYP1A1, CYP1A2 and CYP3A4 mRNA, and to a lesser extent, CYP1B1 and CYP2B6 mRNA in primary human hepatocytes. Chlorpyrifos and DEET also mediated the expression of CYP isoforms, particularly CYP3A4, CYP2B6 and CYP1A1, as shown by CYP3A4-specific protein expression, testosterone metabolism and CYP1Al-specific activity assays. DEET is a mild, while chlorpyrifos is a relatively potent, inducer of adenylate kinase and caspase-3/7, an indicator of apoptosis, while inducing 15-20% and 25-30% cell death, respectively. Therefore, DEET and chlorpyrifos mediated induction of CYP mRNA and functional CYP isoforms together with their cytotoxic potential in human hepatocytes suggests that exposure to chlorpyrifos and/or DEET should be considered in human health impact analysis.
Keywords
Cell-metabolism; Cellular-reactions; Chemical-hypersensitivity; Chemical-indicators; Chemical-reactions; Cytotoxic-effects; Environmental-exposure; Environmental-hazards; Enzymatic-effects; Hepatocytes; Hepatotoxicity; Hormone-activity; Hormones; Liver; Metabolic-disorders; Metabolic-study; Metabolism
Contact
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633
CODEN
DMDIEQ
Publication Date
20080102
Document Type
Journal Article
Funding Type
Cooperative Agreement
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U50-OH-007551
Issue of Publication
3-4
ISSN
0792-5077
Source Name
Drug Metabolism and Drug Interactions
State
MD; NC
Performing Organization
East Carolina University
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