The Impact of Obesity on Proteins Involved in Drug Disposition

  • Author / Creator
    Abdussalam, Ali MA
  • The prevalence of obesity worldwide has increased in the last few decades. The risk of obesity comes from its association with various clinical diseases especially cardiovascular diseases and diabetes. In this thesis, we assessed the expression of some drug metabolizing enzymes and transport proteins in livers and kidneys of rats fed normal rat chow with water or one of three types of high calorie-containing diets. Four groups of rats (10/group) were housed for 14 weeks and they had access either to normal rodent food and water (control), normal rodent chow and high fructose-corn syrup water (HFCS), 45% high fat (FD) diet and water, or 45% FD and HFCS. After 14 weeks, all biochemical and hematological parameters were assayed using standard diagnostic kits. The mRNA levels and protein contents of cytochrome P450 (CYP) enzymes and membrane transporters in rat liver and kidney were determined using real-time PCR and Western blot respectively. There were significant increases in plasma insulin, leptin, triglyceride and cholesterol in each of the high calorie fed groups compared to control group. Relative to the control, the mRNA and/or protein levels of CYP3A1, 3A2, and 2C11 were decreased in the liver of both FD and HFCS/FD groups. Although mean hepatic mRNA of OCT1, MATE1 did not change significantly, the transporters protein levels of OCT1 showed significant decrease in HFCS/FD and for MATE1 the decrease were significant in both FD and HFCS/FD. In renal, there were no significant differences in mRNA levels of Oct1, Oct2, Mate1, and Mdr1 between groups. In contrast, the protein levels were significantly down regulated for OCT1 in HFCS/FD, and for OCT2 in both FD and HFCS/FD. In separate experiment Amiodarone.HCl (AM) biodistribution in presence and absence of dietary induced obesity was studied. To achieve this, two groups have been used. The control group was fed on standard rat chow with normal drinking water and the HFCS/FD group was on high fat diet (45% kcal fat) with 13%w/v HFCS. After 14 weeks, rats in the both groups were given AM 25 mg/kg orally and euthanized by cardiac puncture at different time intervals according to the study protocol. In this single dose oral study, obesity significantly increased plasma concentrations of AM. In HFCS/FD group Liver concentration of AM was higher, however, both lung and heart concentrations was lower compared to control. Desethylamiodarone (DEA) concentrations, a main product of AM metabolism, were lower in plasma, lung and heart but higher in the liver of HFCS/FD compared to control. Our findings suggest that obesity induced by high caloric diet can reduce the expression of some microsomal enzymes and transporter proteins. Hyperlipidemia seems to play a role in this mechanism and that the degree of its effect is enzyme and transporters dependent. These findings could explain some of changes found in biodistribution of AM in obese rats.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
    • Ussher, John (Pharmacy and Pharmaceutical Sciences)
    • Seubert, John (Pharmacy and Pharmaceutical Sciences)