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.
Abu-Qare
Aqel W
AW
Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Elmasry
Eman
E
Abou-Donia
Mohamed B
MB
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