Sandbox PgpWWC: Difference between revisions
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== Function and | == Function, Expression, and History == | ||
As mentioned previously, ABCB1 is located in the liver, kidney, adrenal gland, intestine, BBB, placenta, blood-testis barrier, and blood-ovarian barriers. Furthermore, ABCB1 is overexpressed in tumor cells. The presence of ABCB1 in these locations prevents the entry of toxins into the cells, but also prevents the accumulation of therapeutic drugs. Toxins are effluxed into bile, urine, and the intestinal lumen, in order for excretion from the body.<ref name="Marchetti" /> | As mentioned previously, ABCB1 is located in the liver, kidney, adrenal gland, intestine, BBB, placenta, blood-testis barrier, and blood-ovarian barriers. Furthermore, ABCB1 is overexpressed in tumor cells. The presence of ABCB1 in these locations prevents the entry of toxins into the cells, but also prevents the accumulation of therapeutic drugs. Toxins are effluxed into bile, urine, and the intestinal lumen, in order for excretion from the body.<ref name="Marchetti" /> | ||
The ABCB1 gene is located on Chromosome 7 (region 7q21.12), and codes a protein with 1280 amino acids. <ref name="Wolking"> PMID: 25860377</ref> ABCB1 genetic polymorphisms from the MDR1 gene influence the function of the protein, substrate specificity, and drug-drug interactions. Most variation is caused by single nucleotide polymorphisms (SNPs) that do not often result in a change in the amino acid sequence. Conflicting studies have been published on the extent of the effects of SNPs on ABCB1 expression and activity with various substrates. However, many studies have connected a pre-disposition for certain diseases or cancers with SNPs of ABCB1. Inter-individual variance has also been identified for different ethnicities. Some studies suggest that differences in diet may account for differences in function and activity, although variability in haplotype in populations likely affects the expression as well. Inter individual variance also affects the localization of ABCB1 throughout the body, and recent studies have explored inducers that stimulate the expression in certain endothelial cells.<ref name="Marchetti" /> | The MDR1A gene was originally connected to ABCB1 in the BBB after a study with knockout mice. When the mice were infested with mites, a harmless treatment of the pesticide ivermectin was sprayed on the knockout mice. When the researchers returned the next day, all of the knockout mice were dead while the wild type mice were unaffected. This result lead to the conclusion that the MDR1a knockout mice had a lack of efflux of the ivermectin, a neurotoxin, out of the BBB.<ref name="Schinkel"> PMID: 10837715</ref> The ABCB1 gene is located on Chromosome 7 (region 7q21.12), and codes a protein with 1280 amino acids. <ref name="Wolking"> PMID: 25860377</ref> ABCB1 genetic polymorphisms from the MDR1 gene influence the function of the protein, substrate specificity, and drug-drug interactions. Most variation is caused by single nucleotide polymorphisms (SNPs) that do not often result in a change in the amino acid sequence. Conflicting studies have been published on the extent of the effects of SNPs on ABCB1 expression and activity with various substrates. However, many studies have connected a pre-disposition for certain diseases or cancers with SNPs of ABCB1. Inter-individual variance has also been identified for different ethnicities. Some studies suggest that differences in diet may account for differences in function and activity, although variability in haplotype in populations likely affects the expression as well. Inter individual variance also affects the localization of ABCB1 throughout the body, and recent studies have explored inducers that stimulate the expression in certain endothelial cells.<ref name="Marchetti" /> | ||
Large-scale sequencing programs including the 1000 Genome Project and the Exome Sequencing Project have recorded approximately 8600 SNP variants, consisting of 390 coding sequence variants. These variations could also cause the inter-individual variance by differences in folding that influence the substrate specifictiy and flexibility of the protein. Furthermore, the stability of messenger RNA (mRNA) could be reduced influencing the insertion of the protein into the membrane. The polymorphisms likely effect the pharmacokinetics and drug responses, posing clinical challenges for therapeutic treatments.<ref name="Wolking" /> | Large-scale sequencing programs including the 1000 Genome Project and the Exome Sequencing Project have recorded approximately 8600 SNP variants, consisting of 390 coding sequence variants. These variations could also cause the inter-individual variance by differences in folding that influence the substrate specifictiy and flexibility of the protein. Furthermore, the stability of messenger RNA (mRNA) could be reduced influencing the insertion of the protein into the membrane. The polymorphisms likely effect the pharmacokinetics and drug responses, posing clinical challenges for therapeutic treatments.<ref name="Wolking" /> | ||
== Structure == | == Structure == | ||