Regulation of hepatic drug transporter activity and expression by organochlorine pesticides.

Abstract

Organochlorine (OC) pesticides constitute a major class of persistent and toxic organic pollutants, known to modulate drug-detoxifying enzymes. In the present study, OCs were demonstrated to also alter the activity and expression of human hepatic drug transporters. Activity of the sinusoidal influx transporter OCT1 (organic cation transporter 1) was thus inhibited by endosulfan, chlordane, heptachlor, lindane, and dieldrine, but not by dichlorodiphenyltrichloroethane isomers, whereas those of the canalicular efflux pumps MRP2 (multidrug resistance-associated protein 2) and BCRP (breast cancer resistance protein) were blocked by endosulfan, chlordane, heptachlor, and chlordecone; this latter OC additionally inhibited the multidrug resistance gene 1 (MDR1)/P-glycoprotein (P-gp) activity. OCs, except endosulfan, were next found to induce MDR1/P-gp and MRP2 mRNA expressions in hepatoma HepaRG cells; some of them also upregulated BCRP. By contrast, expression of sinusoidal transporters was not impaired (organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1) or was downregulated (sodium taurocholate co-transporting polypeptide (NTCP) and OCT1). Such regulations of drug transporter activity and expression, depending on the respective nature of OCs and transporters, may contribute to the toxicity of OC pesticides.

• Authors: Simon Bucher, Marc Le Vee, Elodie Jouan, Olivier Fardel
• Journal: Journal of biochemical and molecular toxicology (J Biochem Mol Toxicol) Vol. 28 Issue 3 Pg. 119-28 (Mar 2014) ISSN: 1099-0461 [Electronic] United States
• PMID: 24464585 (Publication Type: Journal Article)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• ABCB1 protein, human
• ABCC2 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Hydrocarbons, Chlorinated
• Liver-Specific Organic Anion Transporter 1
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Organic Anion Transporters
• Organic Anion Transporters, Sodium-Dependent
• Organic Cation Transporter 1
• Pesticides
• SLCO1B1 protein, human
• SLCO2B1 protein, human
• Symporters
• sodium-bile acid cotransporter

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Cell Line (drug effects)
• Cell Survival (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Hydrocarbons, Chlorinated (pharmacology)
• Inactivation, Metabolic
• Liver (cytology, drug effects, metabolism)
• Liver-Specific Organic Anion Transporter 1
• MCF-7 Cells (drug effects)
• Membrane Transport Proteins (metabolism)
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (metabolism)
• Neoplasm Proteins (metabolism)
• Organic Anion Transporters (metabolism)
• Organic Anion Transporters, Sodium-Dependent (genetics, metabolism)
• Organic Cation Transporter 1 (metabolism)
• Pesticides (pharmacology)
• Symporters (genetics, metabolism)