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• W2017106512 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. This notion has attracted enormous scientific interest because the alleged function of P-gp provides 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. Mol. Carcinog. 25:1–13, 1999. © 1999 Wiley-Liss, Inc." @default.
• W2017106512 created "2016-06-24" @default.
• W2017106512 creator A5080825804 @default.
• W2017106512 date "1999-05-01" @default.
• W2017106512 modified "2023-10-15" @default.
• W2017106512 title "A novel hypothesis for the mechanism of action of P-glycoprotein as a multidrug transporter" @default.
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• W2017106512 doi "https://doi.org/10.1002/(sici)1098-2744(199905)25:1<1::aid-mc1>3.0.co;2-1" @default.
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