Important note: Information in this article was accurate in November 2001. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, November 19 & 26, 2001
Michael Greer, Senior Medical Writer
NewsRx -- P-glycoprotein appears to block HIV protease inhibitors from reaching viral targets in the brain, according to researchers in Canada.
"In the central nervous system, the primary targets of the human immunodeficiency virus-1 (HIV-1) are microglia, resulting in a disorder called HIV-1 dementia," explained Gloria Lee and colleagues at the University of Toronto, the University of Montreal, and the Toronto Western Research Institute. "P-glycoprotein (P-gp), a membrane-associated ATP-dependent efflux transporter, limits entry into the brain of numerous xenobiotics, including anti-HIV drugs (i.e., protease inhibitors)."
Lee and coworkers found evidence that parenchymal microglia express functional P-gp, which would cut those cells off from the antiviral protection afforded by protease inhibitors.
The researchers examined MLS-9 cells, derived from murine microglia, with immuncytochemical and western blot analysis. Western blotting with the C219 antibody showed a band in the 170-180 kDa region consistent with the putative size of P-gp, while monoclonal antibody labeling indicated the presence of P-gp on the nuclear envelope and plasma membrane of MLS-9 cells, they reported.
Moreover, exposing these cells to P-gp or ATPase inhibitors significantly increased the accumulation of the P-gp substrate digoxin, study data showed. Exposure to HIV protease inhibitors including indinavir and ritonavir had a similar effect.
MLS-9 expressed mRNA from only one gene associated with P-gp production, mdr1b, while true rat microglia expressed both mdr1a and mdr1b RNA (Functional expression of P-glycoprotein in rat brain microglia, J Pharmacol Exp Ther 2001 Oct;299(1):204-12.
"These results provide the first evidence for the functional expression of P-gp in microglia," Lee and coauthors concluded, "and imply that entry of pharmacological agents, including protease inhibitors, may be prevented within the brain parenchyma, as well as at the blood-brain barrier."
The corresponding author for this report is Reina Bendayan, University of Toronto, Faculty of Pharmacy, Dept. of Pharmaceutical Sciences, 19 Russell St., Toronto, ON M5S 2S2, Canada.
Key points reported in this study include:
This article was prepared by AIDS Weekly editors from staff and other reports.
011112
AW011105
Copyright © 2001 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA. Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 http://www.newsrx.net
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990,2001. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.