ABCMdb

PMID: 15908806

Sparreboom A, Loos WJ, Burger H, Sissung TM, Verweij J, Figg WD, Nooter K, Gelderblom H
Effect of ABCG2 genotype on the oral bioavailability of topotecan.
Cancer Biol Ther. 2005 Jun;4(6):650-8. Epub 2005 Jun 11., [PubMed]

Sentences

No. Mutations Sentence Comment

13 ABCG2 p.Gln141Lys In recent years, various naturally occurring variants in ABCG2 have been identified that affect the function and/or expression of its encoded protein.4-6 In the present pilot study, we prospectively evaluated the potential functional significance of a common single-nucleotide polymorphism (SNP) in ABCG2 (421C>A; Q141K) in a cohort of cancer patients treated with topotecan. Login to comment 41 ABCG2 p.Gln141Lys Human embryonic kidney cells (HEK293) cells transfected with pcDNA3 (HEK293/Neo, control cells), wild-type ABCG2 (HEK293/R) and an ABCG2 Q141K clone (HEK293/5)10 were provided by Dr. Susan E. Bates (National Cancer Institute, Bethesda, MD). Login to comment 75 ABCG2 p.Gln141Lys The studied variant in ABCG2 is a SNP causing a nonsynonymous change in the protein sequence, in which a 421C to A transition at exon 5 leads to a Glutamine to Lysine amino acid substitution at codon 141 (Q141K). Login to comment 80 ABCG2 p.Gln141Lys In vitro transport studies presented here in HEK293 cells transfected with the Q141K variant showed an increase of 30% in the intracellular accumulation of topotecan relative to wild-type ABCG2. Login to comment 84 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys (A) Intracellular accumulation of topotecan in human embryonic kidney cells (HEK293) transfected with pcDNA3 (HEK293/Neo, Control), wild-type ABCG2 (HEK293/R) and an ABCG2 Q141K clone (HEK293/5, Q141K-5). Login to comment 86 ABCG2 p.Gln141Lys (B) Western blot data for ABCG2 expression in control, wild-type ABCG2 and the ABCG2 Q141K clone. Login to comment 87 ABCG2 p.Gln141Lys A B www.landesbioscience.com Cancer Biology & Therapy e Topotecan Pharmacogenetics In support of this theory, Mizuarai6 described recently that the ATPase activity of the Q141K variant, which is localized in the ATP-binding cassette region, was reduced approximately 1.3-fold compared to the activity of the wild type ABCG2. Login to comment 89 ABCG2 p.Gln141Lys However, our finding is not entirely conclusive as the sole contributing factor, since the increased accumulation in the Q141K variant compared to the wild type was not statistically significant (P = 0.16). Login to comment 90 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys Support for additional mechanisms that might be of relevance, including altered protein expression, comes from the presently performed analysis of the duodenal mucosa biopsies; these preliminary data show that the ABCG2 421C>A genotype is possibly related with reduced mRNA expression of ABCG2 and ABCB1 in intestinal enterocytes, although this seems to contradict earlier findings.22 Nonetheless, earlier data obtained in PA317 cells transfected with the Q141K mutant have indicated that intracellular topotecan accumulation was higher than that in cells with wild-type ABCG2, and this was also ascribed in that case to markedly reduced protein expression levels.23 These authors have speculated that substitution of Glutamine for Lysine at amino acid position 141 might alter the tertiary structure of ABCG2, and lead to increased susceptibility to degradation.23 Clearly, further investigation is required to resolve this issue. Login to comment