Pakistan Research Repository

Pakistan Research Repository                                                                

Home

             
Title of Thesis  
BIOCHEMICAL STUDIES ON NEW INHIBITORS OF B-GLUCURONIDASE AND HEPATOTOXIC ACTIVITY OF SOME CHEMICAL CONSTITUENTS  
Author(s)  
SHAHIDA SHUJJAT  
Institute/University/Department Details  
University of Karachi, Karachi/Chemical Sciences  
Status (Published/ Not Published/ In Press etc)  
Published  
Date of Publishing  
2003  
Subject  
Chemistry  
Number of Pages  
108  
   
Keywords (Extracted from title, table of contents and abstract of thesis)  
B-Glucuronidase, Hepatotoxic activity, Detoxification, Xenobiotics, Toxic compounds, Triterpenoides, Withanolides, Bovine liver, E. coli, Structure activity relationship, Enzyme kinetics, Enzyme inhibition, DPPH,  

 

 
Abstract  

B-Glucuronidase plays a very important role in the hydrolysis of B-glucuronides. Glucuronides are formed in the body during the process of detoxification of xenobiotics. A large number of these toxic compounds are eliminated safely from the body as glucuronides. Since B-glucuronidase hydrolyzes these compounds so the inhibitors of this enzyme in body may protect the body from the toxic effects of these compounds. This thesis describes the B-glucuronidase inhibition activities of 21 natural products isolated from a vc1riety of sources and 16 synthetic compounds synthesized by a number of collaborating researchers at the H. E. J. Research Institute of Chemistry. Most of the newly discovered natural" compounds were identified as members of new classes of B-glucuronidase inhibitors such as triterpenoides and withanolides. The enzyme B-glucuronidase used in these studies was from two different sources i.e. bovine liver and E. coli. The enzyme inhibition activity was calculated as IC50 (the concentration of compound that inhibits the enzyme activity by 50%) and Ki values (the dissociation constant). These values were determined to evaluate and compare the potency of various compounds. The majority of these new inhibitors were found to inhibit both the enzymes (bovine liver, E. coli) in micro molar concentration. The inhibition kinetic experiments have been performed for the majority of these compounds and the results of these studies were used to investigate the mechanism of inhibition of individual compounds. It was discovered that these compounds inhibit B-glucuronidase in a concentration dependent manner. Majority of them were found to be of reversible non-competitive and un-competitive inhibitors. Structure-activity relationships (SAR) were studied for different classes of B-glucuronidase inhibitors on the basis of the experimental data. In most of the cases, multiple groups present at different positions of different compounds were found to be responsible for the inhibitory properties of these compounds. Majority of these compounds have shown Ki in micro- and nano-molar ranges. The hepatoxicity studies of some of the compounds which were available in good amount were also carried out in animal models. Many compounds have shown good anti-hepatotoxic activities against CCl4-induced liver intoxication. Antioxidant activity is another area in which the DPPH radical scavenging property of those compounds which have shown B-glucuronidase inhibitory activity and were in good quantity was also determined.

 
   
Download Full Thesis
946.KB

Sr.No Chapter Table of Contents
 
i 180.kbs
136.KB
1 1

Introduction

1
174.KB
2 2 Results and discussion 24
491.KB
3 3 Experimental 91
75.KB
4 4 References 100
89.KB