CHLORPYRIFOS OXON INTERACTS WITH THE MAMMALIAN MULTIDRUG-RESISTANCE PROTEIN, P-GLYCOPROTEIN

Multidrug resistance (MDR) to chemically unrelated therapeutic antican cer agents in mammalian cells is mediated by the overexpression of an ATP-dependent 150- to 180-kD membrane glycoprotein, P-glycoprotein (P- gp). Although the complete physiological role of P-gp is unknown, it i s proposed to function in cellular detoxification of xenobiotics. In t his study, we investigated whether the organophosphorus insecticide ch lorpyrifos (O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate ) or its metabolites interact with P-gp. Immunohistochemical analysis of tissues from male Fischer 344 rats administered chlorpyrifos (7.6 m g/kg gavage) showed increased P-gp expression in the kidney, adrenal, liver, jejunum, and stomach (tissues associated with elimination of xe nobiotics), compared to control tissues. The most prominent increase w as detected in the large bile ducts of the liver and the proximal tubu le region of the kidney. P-gp expression was increased throughout the adrenal medulla and cortex, while a moderate increase was detected in the epithelial layers of the stomach and jejunum. To examine further t he interaction between chlorpyrifos and P-gp, we evaluated whether chl orpyrifos or its active metabolite, chlorpyrifos oxon, could inhibit [ H-3]azidopine labeling of P-gp in MDR1 baculovirus-infected insect S/9 cells. A concentration-dependent inhibition of [H-3]azidopine labelin g of P-gp was detected with chlorpyrifos oxon, while significant inhib ition was not detected with chlorpyrifos. To correlate the binding of chlorpyrifos oxon to P-gp with a biochemical effect, we examined its a bility to stimulate P-gp-mediated ATPase activity in these S/9 cells. Chlorpyrifos oxon stimulated P-gp ATPase activity 1.75 times that of t he positive control (10 mu M verapamil). Taken together, these results suggest that chlorpyrifos oxon interacts with P-gp, and support the h ypothesis that P-gp may play a role in the cellular detoxification of insecticides in mammalian tissues. To our knowledge this is the first report of an organophosphorus insecticide interacting with and increas ing the expression of P-gp.