title: An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics.
abstract: The human ABCB1 protein, (P-glycoprotein or MDR1) is a membrane-bound glycoprotein that harnesses the energy of ATP hydrolysis to drive the unidirectional transport of substrates from the cytoplasm to the extracellular space. As a large range of therapeutic agents are known substrates of ABCB1 protein, its role in the onset of multidrug resistance has been the focus of much research. This role has been of particular interest in the field of pharmacogenomics where genetic variation within the ABCB1 gene, particularly in the form of single nucleotide polymorphisms (SNPs), is believed to contribute to inter-individual variation in ABCB1 function and drug response. In this review we provide an update on the influence of coding region SNPs within the ABCB1 gene on drug pharmacokinetics. By utilizing the crystal structure of the mouse ABCB1 homolog (Abcb1a), which is 87% homologous to the human sequence, we accompany this discussion with a graphical representation of residue location for amino acids corresponding to human ABCB1 coding region SNPs. Also, an assessment of residue conservation, which is calculated following multiple sequence alignment of 11 confirmed sequences of ABCB1 homologs, is presented and discussed. Superimposing a 'heat map' of residue homology to the Abcb1a crystal structure has permitted additional insights into both the conservation of individual residues and the conservation of their immediate surroundings. Such graphical representation of residue location and conservation supplements this update of ABCB1 pharmacogenetics to help clarify the often confounding reports on the influence of ABCB1 polymorphisms on drug pharmacokinetics and response.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wolf
authors.forename: M
authors.initials: M
authors.lastname: Bachtiar
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: T S
authors.initials: TS
authors.lastname: Sim
authors.forename: S S
authors.initials: SS
authors.lastname: Chong
authors.forename: C G L
authors.initials: CG
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000235:genetics*; D000818:Animals; D017124:Conserved Sequence; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D016366:Open Reading Frames / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1