BACKGROUND: ABCG2 is a drug transporter involved in the protection of tissues by actively transporting toxic substances and xenobiotics out of cells. Cancer cells overexpressing the ABCG2 gene show multidrug resistance to mitoxantrone-, methotrexate-, doxorubicin-, and camptothecin-based anticancer drugs, such as topotecan and SN-38. Large interindividual differences have been shown in oral availability and clearance of drugs that are substrates for ABCG2. Variation in the ABCG2 gene, such as single nucleotide polymorphisms (SNPs), can possibly explain the variability in pharmacokinetics of ABCG2 substrates. AIM: This study was performed to screen for SNPs in the ABCG2 gene to determine the frequencies of currently known and previously unknown SNPs in a Dutch population. METHODS: Blood samples were obtained from 100 healthy volunteers to isolate genomic DNA. PCR amplification was performed, followed by DNA sequencing. The population, of which the ethnicity was 93% Caucasian, consisted of 79 female individuals and 21 males. RESULTS: In total, 19 SNPs were found in the ABCG2 gene, of which 7 were previously unknown. The SNPs G8883A in exon 5 and C44168T in exon 14 cause an amino acid change of R160Q and R575X, respectively. Most of the previously unknown SNPs were found in introns. CONCLUSIONS: The results will be used in future studies to explore the influence of the different SNPs on ABCG2 protein expression, activity, and substrate specificity. In addition, the results can be used to study the effects of genetic polymorphisms in the ABCG2 gene on the pharmacokinetic profile of anticancer drugs.
BACKGROUND:ABCG2 is a drug transporter involved in the protection of tissues by actively transporting toxic substances and xenobiotics out of cells. Cancer cells overexpressing the ABCG2 gene show multidrug resistance to mitoxantrone-, methotrexate-, doxorubicin-, and camptothecin-based anticancer drugs, such as topotecan and SN-38. Large interindividual differences have been shown in oral availability and clearance of drugs that are substrates for ABCG2. Variation in the ABCG2 gene, such as single nucleotide polymorphisms (SNPs), can possibly explain the variability in pharmacokinetics of ABCG2 substrates. AIM: This study was performed to screen for SNPs in the ABCG2 gene to determine the frequencies of currently known and previously unknown SNPs in a Dutch population. METHODS: Blood samples were obtained from 100 healthy volunteers to isolate genomic DNA. PCR amplification was performed, followed by DNA sequencing. The population, of which the ethnicity was 93% Caucasian, consisted of 79 female individuals and 21 males. RESULTS: In total, 19 SNPs were found in the ABCG2 gene, of which 7 were previously unknown. The SNPs G8883A in exon 5 and C44168T in exon 14 cause an amino acid change of R160Q and R575X, respectively. Most of the previously unknown SNPs were found in introns. CONCLUSIONS: The results will be used in future studies to explore the influence of the different SNPs on ABCG2 protein expression, activity, and substrate specificity. In addition, the results can be used to study the effects of genetic polymorphisms in the ABCG2 gene on the pharmacokinetic profile of anticancer drugs.
Authors: Antonius E van Herwaarden; Els Wagenaar; Gracia Merino; Johan W Jonker; Hilde Rosing; Jos H Beijnen; Alfred H Schinkel Journal: Mol Cell Biol Date: 2006-12-04 Impact factor: 4.272
Authors: Qiang Zhang; Judy K Cundiff; Sarah D Maria; Robert J McMahon; Jessica G Woo; Barbara S Davidson; Ardythe L Morrow Journal: Proteomes Date: 2013-09-03