Expression of ATP-binding cassette membrane transporters in a HIV-1 transgenic rat model.
P-glycoprotein (P-gp, product of Mdr1a and Mdr1b genes), multidrug resistance associated proteins (Mrps), and breast cancer resistance protein (Bcrp), all members of the ATP-binding cassette (ABC) membrane-associated drug transporters superfamily, can significantly restrict the entry of antiretroviral drugs (ARVs) into organs which exhibit a barrier function such as the central nervous system (CNS) and the male genital tract (MGT). In vitro, HIV-1 viral proteins such as glycoprotein-120 (gp120) and transcriptional transactivator (tat) have been shown to alter the expression of these transporters and ARVs permeability. The objective of this study was to compare mRNA expression of these transporters, in vivo, in several tissues obtained from HIV-1 transgenic rats (Tg-rat) (8 and 24 weeks) with those of age-matched wild-type rats. At 24 weeks, significant changes in several drug transporter mRNA expressions were observed, in particular, in brain, kidney, liver and testes. These findings suggest that HIV-1 viral proteins can alter the expression of ABC drug transporters, in vivo, in the context of HIV-1 and further regulate ARVs permeability in several organs including the CNS and MGT, two sites which have been reported to display very low ARVs permeability in the clinic.
Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Kevin R
KR
Robillard
Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Md Tozammel
MT
Hoque
Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: r.bendayan@utoronto.ca.
Reina
R
Bendayan
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats / Q000235:genetics* / Q000821:virology*; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D014764:Viral Proteins / Q000235:genetics*
D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; D014764:Viral Proteins
ABC drug transporters; HIV-1 transgenic rat model; mRNA expression; qPCR analysis