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

For years, P-glycoprotein (P-gp) has been purported to be a membrane transp orter capable of selectively transporting many (but not all) lipophilic ant icancer drugs with diverse chemical structures. Because the alleged functio ns of P-gp provide a straightforward, near-perfect explanation for the mole cular 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. I n 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 o nly for certain conjugated metabolites (probably sulfates) of the lipophili c 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 resista nce. The culprit is probably the enhanced function of the metabolizing enzy mes for the lipophilic anticancer drugs. This hypothesis also predicts; tha t 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 enzy mes) for the metabolism, detoxification, and disposition of lipophilic endo genous chemicals as well as xenobiotics, including cytotoxic anticancer dru gs. There exists a considerable body of circumstantial evidence in the lite rature that lends strong support to this mechanistic hypothesis of P-gp's a ction as well as to the predicted physiological functions of P-gp. It will be of considerable interest to examine this novel hypothesis experimentally . (C) 1999 Wiley-Liss, Inc.