Shujaat, Shahida (2003) BIOCHEMICAL STUDIES ON NEW INHIBITORS OF B-GLUCURONIDASE AND HEPATOTOXIC ACTIVITY OF SOME CHEMICAL CONSTITUENTS. PhD thesis, University of Karachi, Karachi.
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.
|Item Type:||Thesis (PhD)|
|Uncontrolled Keywords:||B-Glucuronidase, Hepatotoxic activity, Detoxification, Xenobiotics, Toxic compounds, Triterpenoides, Withanolides, Bovine liver, E. coli, Structure activity relationship, Enzyme kinetics, Enzyme inhibition, DPPH,|
|Subjects:||Physical Sciences (f) > Chemistry(f2)|
|Deposited By:||Mr Ghulam Murtaza|
|Deposited On:||16 Jun 2006|
|Last Modified:||04 Oct 2007 20:59|
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