Abstract
The ATP-binding cassette transporter ABCG2 (BCRP and MXR) is involved in the absorption, distribution, and elimination of numerous drugs. Thus, drugs that are able to reduce the activity of ABCG2, e.g., antihypertensive AT1 receptor antagonists (ARBs), may cause drug-drug interactions and compromise drug safety and efficacy. In addition, genetic variability within the ABCG2 gene may influence the ability of the transporter to interact with ARBs. Thus, the aim of this study was to characterize the ARB-ABCG2 interaction in the light of naturally occurring variations (F489L, R482G) or amino acid substitutions with in silico-predicted relevance for the ARB-ABCG2 interaction (Y469A; M483F; Y570A). For this purpose, ABCG2 variants were expressed in HEK293 cells and the impact of ARBs on ABCG2 activity was studied in vitro using the pheophorbide A (PhA) efflux assay. First, we demonstrated that both the F489L and the Y469A substitution, respectively, reduced ABCG2 protein levels in these cells. Moreover, both substitutions enhanced the inhibitory effect of candesartan cilexetil, irbesartan, losartan, and telmisartan on ABCG2-mediated PhA efflux, whereas the R482G substitution blunted the inhibitory effect of candesartan cilexetil and telmisartan in this regard. In contrast, the ARB-ABCG2 interaction was not altered in cells expressing either the M483F or the Y570A variant, respectively. In conclusion, our data indicate that the third transmembrane helix and adjacent regions of ABCG2 may be of major importance for the interaction of ARBs with the ABC transporter. Moreover, we conclude from our data that individuals carrying the F489L polymorphism may be at increased risk of developing ABCG2-related drug-drug interactions in multi-drug regimens involving ARBs.
Highlights
In humans, at least 48 distinct ATP-binding cassette (ABC) transporters have been described that are divided into seven subfamilies (A–G) based on structural similarities and sequence homology (Moitra and Dean, 2011)
Pharmacogenetic Aspects of ARB-ABCG2 Interaction consisting of one hydrophilic nucleotide binding domain (NBD) located in the cytoplasm and one hydrophobic membranespanning domain (MSD), whereas the functional form of ABCG2 is a homodimer with a molecular mass of approximately 144 kDa (Taylor et al, 2017)
We have demonstrated previously that – within the class of ARBs – in particular telmisartan and the prodrug candesartan cilexetil and to a minor extent irbesartan and losartan were able to inhibit the activity of ABC transporters, such as ABCB1, ABCC2, and ABCG2, in vitro (Weiss et al, 2010) and may affect the disposition of further drugs in vivo (Stangier et al, 2000; Bajcetic et al, 2007; Son et al, 2014)
Summary
At least 48 distinct ATP-binding cassette (ABC) transporters have been described that are divided into seven subfamilies (A–G) based on structural similarities and sequence homology (Moitra and Dean, 2011). The ABC transporter ABCG2, known as breast cancer resistance protein (BCRP) or mitoxantrone resistance-associated protein (MXR), was cloned independently in 1998 from both a drug-selected human breast cancer cell line and a human cDNA library (Allikmets et al, 1998; Doyle et al, 1998). Drug-induced inhibition of ABCG2 activity may cause drug-drug-interactions, i.e., increased drug exposure and altered tissue disposition, by reducing ABCG2mediated elimination of substrate drugs at above-mentioned sites In this context, single nucleotide polymorphisms (SNPs) or acquired somatic mutations of ABCG2, e.g., the gain of function variant R482G that has been observed in multidrugresistant cancer cells, may affect the interaction of drugs with the transporter and influence drug distribution as well as drug response and the incidence of drug-drug interactions. Several SNPs and somatic mutations in the ABCG2 gene have been described which may contribute to the considerable pharmacokinetic and pharmacodynamic variability of drugs that are transported by ABCG2 (Erdem et al, 2012; Ieiri, 2012)
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