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

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 CYP1A1-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.

Original languageEnglish (US)
Pages (from-to)237-260
Number of pages24
JournalDrug Metabolism and Drug Interactions
Volume23
Issue number3-4
StatePublished - 2008

Fingerprint

DEET
Chlorpyrifos
Enzyme Induction
Cytochrome P-450 Enzyme System
Hepatocytes
Cytochrome P-450 CYP3A
Pesticides
Cytochrome P-450 CYP1A1
Protein Isoforms
Cytochrome P-450 CYP1A2
Messenger RNA
Caspase 7
Adenylate Kinase
Xenobiotics
Caspase 3
Pharmaceutical Preparations
Testosterone
Cell Death
Apoptosis
Health

Keywords

  • Chlorpyrifos
  • CYP isoforms
  • Cytotoxicity
  • DEET
  • Human hepatocytes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Medicine(all)

Cite this

Enzyme induction and cytotoxicity in human hepatocytes by chlorpyrifos and N,N-diethyl-m-toluamide (DEET). / Das, Parikshit C.; Cao, Yan; Rose, Randy L.; Cherrington, Nathan J; Hodgson, Ernest.

In: Drug Metabolism and Drug Interactions, Vol. 23, No. 3-4, 2008, p. 237-260.

Research output: Contribution to journalArticle

Das, Parikshit C. ; Cao, Yan ; Rose, Randy L. ; Cherrington, Nathan J ; Hodgson, Ernest. / Enzyme induction and cytotoxicity in human hepatocytes by chlorpyrifos and N,N-diethyl-m-toluamide (DEET). In: Drug Metabolism and Drug Interactions. 2008 ; Vol. 23, No. 3-4. pp. 237-260.
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