Increased expression of MDR1 mRNAs and P-glycoprotein in placentas from HIV-1 infected women.
P-glycoprotein transports several compounds including protease inhibitors, actually used in the clinical management of HIV-1 infection. Since P-glycoprotein is expressed in placental trophoblasts, its efflux activity could interfere with placental transfer of antiretrovirals. The purpose of this study was to investigate the expression of P-gp-encoding MDR1 gene and P-gp itself in full-term placentas from uninfected (n=35) and HIV-1 infected women (n=24). MDR1 transcripts were quantified by real-time PCR using relative (MDR1 normalized upon 28S levels) and absolute (copy number) determinations. P-glycoprotein localization and expression were evaluated by immunohistochemistry and western blot analysis, respectively. Relative or absolute PCR quantification showed a significant 3.3-fold (p<0.0009) or 3.7-fold (p<0.0002) mean increase in MDR1 placental transcription in HIV-infected compared to non-infected women, respectively. Ratios of individual HIV-positive values to HIV-negative mean ranged from 0.1 to 21.8. Moreover a significant 2.5-fold increased expression of immunoreactive P-glycoprotein was evidenced in placentas from HIV-infected women (p<0.0001). This MDR1 overexpression was observed in a similar extent in placentas from pregnant women treated with Zidovudine alone or in combination with Nelfinavir and/or Lamivudine. Our findings suggest that P-glycoprotein in placentas from HIV-infected women would contribute to modulate the materno-fetal transport of antiretrovirals across the placental barrier and consequently diminish fetal exposure to these compounds.
Camus
M
M
Department of Clinical Pharmacy, UPRES EA 2706, University of Pharmaceutical Sciences, Paris XI, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. marysecamus@yahoo.fr
Deloménie
C
C
Didier
N
N
Faye
A
A
Gil
S
S
Dauge
M-C
MC
Mabondzo
A
A
Farinotti
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D005260:Female; D015870:Gene Expression / Q000235:genetics* / Q000502:physiology; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D010920:Placenta / Q000378:metabolism* / Q000821:virology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger