Date of Award

2016

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Fatemeh Akhlaghi

Abstract

Background: Human carboxylesterase 1, CES1, is a phase I drug metabolizing enzyme that catalyzes the hydrolysis of about 20% of therapeutic agents. Factors, such as metabolic syndrome, ethnicity, gender and genetic polymorphism can influence the activity and/or the expression of drug metabolizing enzymes. Consequently, these factors can affect the pharmacokinetics of drugs leading to toxicity or therapeutic failure.

Objective: The objective of our study is to investigate the possible influence of ethnicity, gender, age, genetic polymorphism, metabolic syndrome or fatty liver on CES1 gene expression and activity.

Methods: Expression of CES1 hepatic mRNA was measured in 89 human livers using RT-PCR techniques. Enzymatic activity of CES1 was measured in S9 fractions and cytosols obtained from 40 and 96 human liver donors, respectively. The hydrolysis rates of two CES1 specific substrates clopidogrel and oseltamivir to their corresponding carboxylic acids were measured using LC-MS/MS methods. Statistical analyses were performed to compare between different groups.

Results and Conclusions: Our data showed that diabetic subjects had less CES1 hydrolytic efficiency although our data is limited by the small sample size. In addition, African American group had significantly higher CES1 activity as compared to Caucasian group. This result provides potential explanation to the clinical observation that African Americans subjects exhibit higher resistance to the CES1 substrates clopidogrel.

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