Electronic Theses and Dissertations

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Browsing Electronic Theses and Dissertations by Author "Abdel-Rahman, Sherif Z"

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    Biological and Functional Consequences of Single Nucleotide Polymorphisms of the O6-Methylguanine-DNA-Methyltransferase Gene
    Cross, Courtney 1981-; Abdel-Rahman, Sherif Z; Ward, Jonathan B; Moslen, Mary; Khan, Firoze; El-Zein, Randa; Christiani, David C
    Single nucleotide polymorphisms (SNPs) in DNA repair genes could alter the transcriptional levels, structure and function of DNA repair proteins and alter DNA repair proficiency. Consequently, these SNPs could significantly influence the level of genetic damage, which is an early critical factor in the cascade of events leading to cancer. Molecular epidemiological studies indicate that SNPs in the 06-Methylguanine-DNA-Methyltransferase (MGMT) gene, which repairs alkyl adducts at the 06-position of guanine, may be associated with an increased risk of lung cancer. However, the functional and biological significance of these SNPs has yet to be systematically characterized. We used two biologically relevant endpoints in an exposed population of 350 individuals to determine the association between genetic damage and SNPs in MGMT; chromosome aberrations to examine macrolesions, and mutation frequency to examine microlesions. In addition, we used the luciferase reporter assay to determine effects of SNPs in the promoter/enhancer region of MGMT on promoter activity. Coding SNPs had a marginal effect on macrolesion damage after exposure to alkylating agents. However a strong effect of coding SNPs on microlesion damage was observed. The luciferase expression data demonstrated a significant increase in promoter activity in the presence of the enhancer SNP compared to the wild-type form. This indicates that, in a biological system, inheritance of one copy of these SNPs could affect the level of genetic damage, especially after accumulated exposure to alkylating agents. While the coding SNPs evaluated are predicted to be detrimental, as indicated by the accumulation of genetic damage, the promoter/enhancer SNP evaluated may be protective as levels of cellular protein would be increased.
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    Pharmacokinetics of Bupropion and its Pharmacologically Active Metabolites in Pregnancy
    Fokina, Valentina Mikhaylovna; Ahmed, Mahmoud S; Nanovskaya, Tatiana N; Abdel-Rahman, Sherif Z; Rytting, Erik; Snodgrass, Wayne R; Abdel-Rahman, Susan M
    Bupropion, an antidepressant and anti-smoking medication, is used for treatment of depression during pregnancy, however its efficacy as a smoking cessation aid in pregnancy has not been confirmed. The drug is extensively biotransformed by liver with the formation of pharmacologically active metabolites, namely hydroxybupropion (OHBUP), threo- (TB) and erythrohydrobupropion (EB). CYP2B6 is the primary enzyme catalyzing the formation of OHBUP; the latter is the main plasma metabolite of bupropion and is thought to contribute majorly to pharmacological efficacy of the drug. CYP2C19 enzyme is involved in hydroxylation of bupropion, as well as TB and EB. Pregnancy-associated changes in maternal physiology may alter the pharmacokinetics of bupropion and thus influence the efficacy of bupropion in promoting cessation in pregnant smokers. Therefore, the primary objective of this study was to evaluate the effect of pregnancy on bupropion biodisposition. In addition, we studied the impact of functional genetic variants of CYP2B6 and CYP2C19 on bupropion pharmacokinetics in pregnancy. Our data indicated that the isoform-specific effect of pregnancy on bupropion-metabolizing enzymes and changes in renal function during pregnancy could collectively result in slight increase of bupropion apparent oral clearance; however, no changes in the plasma levels of OHBUP were evident. Further, our data demonstrated that the effect of CYP2B6*6 (reduced function allele) and CYP2C19*2 (loss-of-function allele) on bupropion biodisposition in pregnancy are similar to those observed in the non-pregnant state. We also investigated the in vivo placental transfer of the drug and its metabolites. For this purpose, the drug and its metabolites were determined in the matching maternal-umbilical cord blood plasma samples collected at delivery from pregnant women treated with bupropion for depression during pregnancy. The levels of OHBUP, TB, and, with a few exceptions, bupropion, in the umbilical cord venous plasma were lower than those in the matching maternal plasma, suggesting limited fetal exposure. In addition, we found that the concentrations of OHBUP and TB in the fetal circulation could be predicted from those in the maternal plasma. Further, bupropion and its metabolites were determined in the amniotic fluid, suggesting additional pathway of fetal exposure to maternally administered bupropion.