title: HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition.
abstract: This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV(+)) subjects, and HIV(+) subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of CYP3A4 and ABCC2/MRP2 in the HIV(+) ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV(+) naive group than in the control group and was partially restored to baseline levels in HIV(+) subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV(+) subjects on ART relative to HIV(+) ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV(+) subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV(+) subjects. This has clinical implications when using data from healthy volunteers to guide ART.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Olena
authors.initials: O
authors.lastname: Kis
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: Sumathi
authors.initials: S
authors.lastname: Sankaran-Walters
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M Tozammel
authors.initials: MT
authors.lastname: Hoque
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Walmsley
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada r.bendayan@utoronto.ca.
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D019380:Anti-HIV Agents; D051544:Cytochrome P-450 CYP3A; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human