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 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.
Zhu
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Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208, USA.
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001693:Biological Transport, Active; D001711:Biotransformation; D002462:Cell Membrane / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR; D006801:Humans; D008954:Models, Biological; D013431:Sulfates / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D013431:Sulfates