Characterization of human cytochrome P450 induction by pesticides.
Pesticides are a large group of structurally diverse toxic chemicals. The toxicity may be modified by cytochrome P450 (CYP) enzyme activity. In the current study, we have investigated effects and mechanisms of 24 structurally varying pesticides on human CYP expression. Many pesticides were found to efficiently activate human pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR). Out of the 24 compounds tested, 14 increased PXR- and 15 CAR-mediated luciferase activities at least 2-fold. While PXR was predominantly activated by pyrethroids, CAR was, in addition to pyrethroids, well activated by organophosphates and several carbamates. Induction of CYP mRNAs and catalytic activities was studied in the metabolically competent, human derived HepaRG cell line. CYP3A4 mRNA was induced most powerfully by pyrethroids; 50 μM cypermethrin increased CYP3A4 mRNA 35-fold. CYP2B6 was induced fairly equally by organophosphate, carbamate and pyrethroid compounds. Induction of CYP3A4 and CYP2B6 by these compound classes paralleled their effects on PXR and CAR. The urea herbicide diuron and the triazine herbicide atrazine induced CYP2B6 mRNA more than 10-fold, but did not activate CAR indicating that some pesticides may induce CYP2B6 via CAR-independent mechanisms. CYP catalyzed activities were induced much less than the corresponding mRNAs. At least in some cases, this is probably due to significant inhibition of CYP enzymes by the studied pesticides. Compared with human CAR activation and CYP2B6 expression, pesticides had much less effect on mouse CAR and CYP2B10 mRNA. Altogether, pesticides were found to be powerful human CYP inducers acting through both PXR and CAR.
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland. Khaled.megahed@oulu.fi
Khaled
K
Abass
Virpi
V
Lämsä
Petri
P
Reponen
Jenni
J
Küblbeck
Paavo
P
Honkakoski
Sampo
S
Mattila
Olavi
O
Pelkonen
Jukka
J
Hakkola
D000818:Animals; D002219:Carbamates / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010575:Pesticides / Q000494:pharmacology* / Q000633:toxicity; D000077297:Pregnane X Receptor; D011722:Pyrethrins / Q000494:pharmacology / Q000633:toxicity; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000096:biosynthesis
D002219:Carbamates; D000090702:Constitutive Androstane Receptor; D010575:Pesticides; D000077297:Pregnane X Receptor; D011722:Pyrethrins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase