title: The multidrug resistance 1 gene Abcb1 in brain and placenta: comparative analysis in human and guinea pig.
abstract: The Multidrug Resistance 1 (MDR1; alternatively ABCB1) gene product P-glycoprotein (P-gp), an ATP binding cassette transporter, extrudes multiple endogenous and exogenous substrates from the cell, playing an important role in normal physiology and xenobiotic distribution and bioavailability. To date, the predominant animal models used to investigate the role of P-gp have been the mouse and rat, which have two distinct genes, Abcb1a and Abcb1b. In contrast, the human has a single gene, ABCB1, for which only a single isoform has been validated. We and others have previously shown important differences between Abcb1a and Abcb1b, limiting the extrapolation from rodent findings to the human. Since the guinea pig has a relatively long gestation, hemomonochorial placentation and neuroanatomically mature offspring, it is more similar to the human, and may provide a more comparable model for investigating the regulation of P-gp in the brain and placenta, however, to date, the Abcb1 gene in the guinea pig remains to be characterized. The placenta and fetal brain are barrier sites that express P-gp and that play a critical role of protection of the fetus and the fetal brain from maternally administered drugs and other xenobiotics. Using RNA sequencing (RNA-seq), reverse transcription-polymerase chain reaction (RT-PCR) and quantitative PCR (QPCR) to sequence the expressed isoforms of guinea pig Abcb1, we demonstrate that like the human, the guinea pig genome contains one gene for Abcb1 but that it is expressed as at least three different isoforms via alternative splicing and alternate exon usage. Further, we demonstrate that these isoforms are more closely related to human than to rat or mouse isoforms. This striking, overall similarity and evolutionary relatedness between guinea pig Abcb1 and human ABCB1 indicate that the guinea pig represents a relevant animal model for investigating the function and regulation of P-gp in the placenta and brain.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Pappas
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Petropoulos
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Sackler Program for Epigenetics and Psychobiology and McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Suderman
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Moisiadis
authors.affiliation: Departments of Psychiatry, Human Genetics and Neurology & Neurosurgery, McGill University, Montreal, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada; Departments of Obstetrics and Gynecology and Medicine, University of Toronto, Toronto, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D009928:Organ Specificity; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D013045:Species Specificity
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020033:Protein Isoforms