| Pesticide resistance is a major problem when controlling various types of insects. The tobacco budworm (Heliothis virescens) has developed resistance to nearly every type of pesticide including organochlorines, organophosphorus esters, carbamates, and synthetic pyrethroids. Resistance to one pesticide commonly results in resistance to other structurally unrelated pesticides, often referred to as "cross-resistance." Conceptually, "cross-resistance" parallels multidrug resistance (MDR); whereby, resistance to one drug is accompanied by the simultaneous resistance to a variety of structurally unrelated compounds. MDR is mediated by the over-expression of an ATP-dependent glycoprotein, P-glycoprotein (P-gp).; The purpose of this study was to examine the hypothesis that a pesticide induces MDR and that the MDR protein, P-gp, is involved in pesticide resistance. This study demonstrated that the organophosphorus pesticide, chlorpyrifos, (O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate), increased P-gp expression in the tissues along the digestive tract in Fischer 344 rats. Azidopine labeling and ATPase experiments demonstrated that the active metabolite, chlorpyrifos oxon, bound to P-gp and stimulated P-gp ATPase activity. This study was the first report of an organophosphorus pesticide interacting with and increasing the expression of P-gp.; This association with P-gp led to the examination of the role of P-gp in pesticide resistance. A P-gp homolog was identified in resistant and susceptible tobacco budworms. P-gp expression was increased approximately 1.8- to 6.4-fold in the resistant populations. The tobacco budworm P-gp homolog was glycosylated and localized primarily in the cuticle and the fat body. As with other mechanisms of resistance, P-gp expression increased with tobacco budworm development. Inhibiting P-gp in the resistant population with quinidine decreased the LD{dollar}sb{lcub}50{rcub}{dollar} for thiodicarb by a factor of 12.5 and increased the rate of ({dollar}sp{lcub}14{rcub}{dollar}C) thiodicarb accumulation by three-fold.; This study is the first to identify P-gp in tobacco budworms and to characterize its role in pesticide resistance. Additionally, this study demonstrated the mechanism of P-gp in pesticide resistance. The ability to inhibit P-gp and significantly decrease the LD{dollar}sb{lcub}50{rcub}{dollar} has an important implication in the troublesome problem of pesticide resistance. Formulations of P-gp inhibitors with certain pesticides may allow for a decreased dosage of pesticides to achieve adequate insect control in agriculture. |
