Search drugs of misuse as keywords on MyScienceWork's publications...

Candidate Deirdre Thajam University of Manchester Degree PhD May 2013Title The Role of Multidrug Resistance Proteins in Determining Fetal Susceptibility to Drugs of Misuse Background- Negative outcomes from fetal exposure to maternal dug use include Neonatal Abstinence Syndrome NAS and altered development the unpredictability of which suggests a biological element as yet not accounted for The manner in which the human placenta protects the fetus from xenobiotics such as drugs of misuse is not completely characterised However Adenosine Triphosphate Binding Cassette ABC transporters in placentae have demonstrated their ability to efflux xenobiotics away from the fetal vascular compartment leading to lower concentrations than in the maternal compartment and some commonly used drugs have been shown to be substrates for these proteins e g methadone It is suggested that polymorphisms in the genes that encode these transporter proteins may alter their expression and or function Hypothesis- Polymorphisms SNPs in the ABC transporters ABCB1 ABCG2 ABCC1 and ABCC2 change protein expression and or function leading to increased fetal exposure demonstrated by increased signs of NAS and or altered development Objectives- To determine if genotype alters protein expression and whether there is a relationship between the level of placental multidrug resistance protein P-glycoprotein P-gp Breast Cancer Resistance Protein BCRP Multidrug Resistance Associated Proteins MRP1 and MRP2 expression and neonatal and or developmental outcomes Methods- Drug using women were recruited In the immediate postnatal period placental tissue cord blood and maternal hair samples were taken Hair was analysed to determine drug use in the preceding 3 months immunoblotting determined the level of P-gp BCRP MRP1 and MRP2 protein expression Sequenom MassExtend Array produced genotypes from DNA obtained from cord blood Infants were assessed for NAS at birth 3 days and 3 weeks At 8 months and 1 year development was assessed using the Griffiths Mental Development Scales Plink was used to determine statistically significant associations between genotype and outcome phenotypes Results- The level of fetal drug exposure did not predict the need for pharmacological treatment for NAS 32 polymorphisms with significant associations to outcome measures were identified 4 SNPs significantly altered protein expression 3 for P-gp and 1 for MRP1 41 SNPs were associated with changes across 4 of the 5 GMDS subscales Discussion- No clear relationship between MDRP protein expression and neonatal outcome was noted However fetal genotype did influence the expression of P-gp and MRP1 and genotype across all four proteins was associated with significant changes in the measures of infant development This was a small study and as such generation of susceptible haplotypes was not possible However the data generated do support the concept Further larger and longer term prospective studies building on the experience reported in this thesis are necessary to generate more data in order to identify haplotypes leading to increased fetal susceptibility to drug exposure

Publication search with drugs of misuse as keyword

The Role of Multidrug Resistance Proteins in Determining Fetal Susceptibility to Drugs of Misuse

Publication search
with drugs of misuse as keyword