SPECIFIC INHIBITORS DISTINGUISH THE CHLORIDE CHANNEL AND DRUG TRANSPORTER FUNCTIONS ASSOCIATED WITH THE HUMAN MULTIDRUG-RESISTANCE P-GLYCOPROTEIN

Expression of the human multidrug resistance P-glycoprotein is associa ted with two activities, active drug transport and a volume-regulated chloride channel. In this study we define four classes of compound, ba sed on their differential effects on these two activities. Class I com pounds are substrates transported by P-glycoprotein. They also prevent channel activation when added to the cytoplasmic face of the membrane . Class II compounds include reversers of multidrug resistance such as verapamil. These compounds inhibit drug transport and block the chlor ide channel when added to the outer face of the membrane. Class III co mpounds include conventional channel blockers which block the chloride channel but do not influence drug transport. Class IV compounds, for example cyclosporin A, appear to inhibit drug transport but do not aff ect chloride channel activity. These findings have implications for th e relationship between the channel and transporter functions associate d with P-glycoprotein expression, and for the development of clinical agents which reverse multidrug resistance.