A novel hypothesis for the mechanism of action of P-glycoprotein as a multidrug transporter

Abstract

For years, P-glycoprotein (P-gp) has been purported to be a membrane transporter capable of selectively transporting many (but not all) lipophilic anticancer drugs with diverse chemical structures. Because the alleged functions of P-gp provide a straightforward, near-perfect explanation for the molecular mechanism of multidrug resistance associated with P-gp overexpression. However, the exact molecular mechanism for P-gp's purported function has never been clearly understood since its initial discovery some 20 yr ago. In this paper, I develop a novel working hypothesis regarding the mechanism of P-gp's action and suggest that P-gp is an energy-dependent efflux pump only for certain conjugated metabolites (probably sulfates) of the lipophilic anticancer drugs but not for the parent compounds, as was always claimed. According to this hypothesis, P-gp overexpression in most cases is not the "culprit" but instead an "accomplice" in P-gp-associated multidrug resistance. The culprit is probably the enhanced function of the metabolizing enzymes for the lipophilic anticancer drugs. This hypothesis also predicts that one of the important physiological functions of P-gp is to be part of an intracellular machinery (together with the phase I and II metabolizing enzymes) for the metabolism, detoxification, and disposition of lipophilic endogenous chemicals as well as xenobiotics, including cytotoxic anticancer drugs. There exists a considerable body of circumstantial evidence in the literature that lends strong support to this mechanistic hypothesis of P-gp's action as well as to the predicted physiological functions of P-gp. It will be of considerable interest to examine this novel hypothesis experimentally.

Influence of verapamil on the efflux and metabolism of 14C moxidectin in cultured rat hepatocytes

“…It was confirmed in rats (Alvinerie et al ., 1999b) in which an enhanced absorption and/or diminished elimination of pour‐on ivermectin formulation by coadministration of verapamil was reported. Our results also corroborated the hypothesis developed by Zhu (1999) based on the necessary enzymatic biotransformations (phase I oxidative metabolism followed by phase II conjugative metabolism mediated by cytochromes P450) of Pgp substrates before their elimination by Pgp. Indeed, verapamil was subjected to extensive oxidative metabolism mediated by cytochromes P450 and so the inhibitory effect on Pgp registered after 8 h should be because of the verapamil metabolites.…”

“…This experiment illustrated the interest of an in vitro model which expresses both Pgp and cytochromes P450 3 A because of the shared location in different tissues as well as the significant overlap in their substrate/inhibitor specificities (Zhu, 1999). This interaction is of great interest in endectocide pharmacokinetics because of its impact on bioavailability.…”

Contribution of Efflux Pump Activity to the Delivery of Pulmonary Therapeutics

“…Evidence for this is supported by the work of Valverde et al, [65]. The latest mechanism of Pgp transport proposes that the protein functions as an energydependent pump specifically for conjugated metabolites, and not their unconjugated precursors [66].…”

The suppressed expression and functional activity of hepatic P-glycoprotein in rats with protein–calorie malnutrition

“…The in vitro uptake of daunomycin, a representative substrate of P‐gp,10 into cLPM vesicles was determined by a rapid filtration technique using vesicles prepared from control and PCM rats as described elsewhere 9. The net ATP‐dependent uptake was calculated by subtracting the values determined in the absence of ATP from those in the presence of ATP.…”