The multidrug transporter ABCG2: still more questions than answers

Horsey, Aaron J.; Cox, Megan H.; Sarwat, Sunehera; Kerr, Ian D.

doi:10.1042/bst20160014

Cited by 86 publications

(62 citation statements)

References 63 publications

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“…This assertion is supported by the susceptibility of ABCG2 knockout mice to diet-induced phototoxicity and protoporphyria 15. It is expressed in the small intestine (excretion and limiting absorption), blood–brain and blood–placental barriers (mediating distribution), liver and kidney (elimination and excretion), and mammary gland (transporting into milk) 16. The pattern of ABCG2 expression is consistent with its role as a uric acid efflux transporter (reviewed in reference 17).…”

Section: Introductionmentioning

confidence: 83%

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Cleophas¹,

Joosten²,

Stamp³

et al. 2017

PGPM

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As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.

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Section: Introductionmentioning

confidence: 83%

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Cleophas¹,

Joosten²,

Stamp³

et al. 2017

PGPM

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“…The ABC subfamily G isoform 2 (ABCG2) protein is a MDR pump with a wide distribution in the human body, which is found in the small intestine, blood-brain barrier, blood-placenta barrier, liver canalicular membranes, proximal tubule cells of the kidney, and the mammary gland (Horsey et al, 2016). The functions of ABCG2 at its widespread locations are summarized in Table 1, and to illustrate the diversity of its substrate repertoire endogenous and xenobiotic substrates are shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Poorer outcomes have been shown in large B-cell lymphoma (Kim et al, 2009b) and acute myeloid leukemia in patients with higher ABCG2 levels (Van den Heuvel-Eibrink et al, 2002;Benderra et al, 2004). ABCG2 also has an established link to survival rates and therapy response in small-cell and non-small-cell lung cancer (see Mo and Zhang, 2012;Horsey et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of the Multidrug Pump ABCG2: A Systematic Review of Their Effect on Protein Expression, Function, and Drug Pharmacokinetics

2018

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The widespread expression and polyspecificity of the multidrug ABCG2 efflux transporter make it an important determinant of the pharmacokinetics of a variety of substrate drugs. Null ABCG2 expression has been linked to the Junior blood group. Polymorphisms affecting the expression or function of ABCG2 may have clinically important roles in drug disposition and efficacy. The most well-studied single nucleotide polymorphism (SNP), Q141K (421C>A), is shown to decrease ABCG2 expression and activity, resulting in increased total drug exposure and decreased resistance to various substrates. The effect of Q141K can be rationalized by inspection of the ABCG2 structure, and the effects of this SNP on protein processing may make it a target for pharmacological intervention. The V12M SNP (34G>A) appears to improve outcomes in cancer patients treated with tyrosine kinase inhibitors, but the reasons for this are yet to be established, and this residue's role in the mechanism of the protein is unexplored by current biochemical and structural approaches. Research into the less-common polymorphisms is confined to in vitro studies, with several polymorphisms shown to decrease resistance to anticancer agents such as SN-38 and mitoxantrone. In this review, we present a systematic analysis of the effects of ABCG2 polymorphisms on ABCG2 function and drug pharmacokinetics. Where possible, we use recent structural advances to present a molecular interpretation of the effects of SNPs and indicate where we need further in vitro experiments to fully resolve how SNPs impact ABCG2 function.

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“…The human ABCG2 has been studied extensively, because of early reports associating ABCG2 overexpression with the development of cancer resistance to drugs inhibiting the cell cycle by intercalating into DNA (CHEN et al 1990). The consensus for the mechanism of action of ABCG2 is its direct activity in exporting drugs from cells, however the apparent lack of specificity in the transported molecules is puzzling: more than 200 substrates have been described for ABCG2 (HORSEY et al 2016). Amongst these substrates, one is riboflavin (VAN HERWAARDEN et al 2007), another is cGMP (DE WOLF et al 2007;EVANS et al 2008).…”

Section: On the Function Of The Abcg2 Transportersmentioning

confidence: 99%

Zinc storage granules in the Malpighian tubules ofDrosophila melanogaster

Tejeda-Guzmán

Rosas‐Arellano

Kröll

et al. 2017

Preprint

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Membrane transporters and sequestration mechanisms concentrate metal ions differentially into discrete subcellular microenvironments for usage in protein cofactors, signaling, storage, or excretion. Here we identify zinc storage granules as the insect’s major zinc reservoir in primary Malpighian tubule epithelial cells of Drosophila melanogaster. The concerted action of Adaptor Protein-3, Rab32, HOPS and BLOC complexes as well as of the white-scarlet (ABCG2-like) and ZnT35C transporters is required for zinc storage granule biogenesis. Due to similar lysosome related organelle defects, patients with Hermansky-Pudlak syndrome may lack zinc granules in beta pancreatic cells, intestinal paneth cells and presynaptic vesicles of hippocampal mossy fibers.

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The multidrug transporter ABCG2: still more questions than answers

Cited by 86 publications

References 63 publications

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Polymorphisms of the Multidrug Pump ABCG2: A Systematic Review of Their Effect on Protein Expression, Function, and Drug Pharmacokinetics

Zinc storage granules in the Malpighian tubules ofDrosophila melanogaster

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