A role for P-glycoprotein in environmental toxicology.
P-Glycoprotein (P-gp) is a transmembrane protein, playing significant roles in the process of drug discovery and development and in pest resistance to pesticides. P-gp affects absorption, disposition, and elimination of different compounds and is mainly expressed in intestines, liver, kidneys, heart, colon, and placenta. The expression of P-gp in the blood-brain barrier (BBB) has been associated with the restricted access of many compounds to the central nervous system. Generated knockout mice by disruption of mdr 1a gene, encoding for P-gp, showed that this protein was expressed in the BBB. The absence or the low levels of P-gp elevated drug concentrations in tissues and decreased drug elimination. P-gp is responsible for resistance of cells to agents, particularly the anticancer drugs, by removing these drugs from cells. Increased expression of P-gp is implicated in decreased HIV drug availability at certain intracellular sites. The role of P-gp in affecting efficacy and toxicity of environmental toxicants such as pesticides and heavy metals has not been adequately investigated. Studies showed that P-gp contributes to resistance to pesticides in certain pest species, and to decrease toxicity by removing compounds from cells in mammals. Placental drug-transporting P-gp plays a significant role in limiting the transport of toxicants such as potential teratogens to the fetus. Several in vitro or in vivo assays, including using P-gp knockout or naturally deficient mice, were described for testing P-gp modulators. The role of P-gp following concurrent exposure to more multiple compounds needs further research. P-gp modulators should be carefully used, since some modulators that reverse P-gp efflux action in vitro may lead to alterations of tissue function and increase toxicity of xenobiotics in normal tissues. Recent reports from the pharmaceutical studies on the significance of P-gp as transporters in altering the efficacy and toxicity clearly highlight the need for further research in interaction with environmental toxicants.
Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Aqel W
AW
Abu-Qare
Eman
E
Elmasry
Mohamed B
MB
Abou-Donia
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay; D001812:Blood-Brain Barrier; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015262:Xenobiotics / Q000009:adverse effects* / Q000378:metabolism* / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System