Synthesis and evaluation of novel hepatoprotective L-cysteine prodrugs

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Title Synthesis and evaluation of novel hepatoprotective L-cysteine prodrugs
Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Phaneuf, Holly Louise
Date 1997-12
Description Numerous deleterious physiological effects result from cellular depletion of glutathione (GSH). GSH is abundant in living systems and exerts several protective functions. Reduction of the normally high levels of GSH in cells results from a wide array of endogenous and exogenous factors. The liver is frequently vulnerable to GSH depletion by exposure to toxins. Developing novel agents that increase GSH in the liver has been the primary goal of this work. Since GSH cannot be taken up by cells and is quickly catabolized, prodrug forms of its constituent L-cysteine, which supports the biosynthesis of GSH, have proved a successful therapeutic alternative. Prodrug versions of L-cysteine are required to overcome the toxicity of L-cystelne itself. Drug targeting as a means of directing agents to particular cells or organs is well established in the case of hepatocyte targeting. The hepatic asialoglycoprotein receptor (ASGPR) recognizes molecules bearing galactose moieties, which is followed by cellular uptake. Three L-cysteine prodrugs possessing galactose were synthesized using the condensation of L-cysteine with aldoses to form a thiazolidine carboxylic acid (TCA). TCAs dissociate nonenzymatically over time and have previously demonstrated GSH-maintaining ability. The galactose-bearing prodrugs were developed with the aim of increasing liver L-cysteine prodrug through ASGPR targeting. Two related glucose-bearing prodrugs were synthesized as controls. Prodrug toxicity was not seen in mice and apparent in cells only at high concentrations after prolonged exposures. Biodistribution of prodrugs in mice and protection using hepatocytes with and without the ASGPR were used to indicate targeting. Protection studies used acetaminophen (APAP), which is well documented as a GSH-depleting hepatotoxin. All five prodrugs protected against APAP, yet prodrug targeting is ambiguous. Additional protection mechanisms involving Phase II enzyme induction were addressed, because thiol induction has been documented. Prodrugs did not cause induction at the doses given, with the possible exception of one, but this was complicated by APAP induction. Studies determining liver and kidney GSH imply that the most conspicuous protection mechanism is the prevention of GSH depletion by APAP. Although ASGPR targeting is not immediately obvious from these studies, the principal goal, the development of novel hepatoprotective GSH-maintaining agents, was achieved.
Type Text
Publisher University of Utah
Subject Physiological; Glutathione
Subject MESH Prodrugs; Liver Diseases
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Synthesis and evaluation of novel hepatoprotective L-cysteine prodrugs". Spencer S. Eccles Health Sciences Library. Print version of "SymText Synthesis and evaluation of novel hepatoprotective L-cysteine prodrugs". available at J. Willard Marriott Library Special Collection RM31.5 1997 .P43.
Rights Management © Holly Louise Phaneuf.
Format application/pdf
Format Medium application/pdf
Format Extent 1,831,587 bytes
Identifier undthes,4542
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship National Institutes of Health and the Universtiy of Utah.
Master File Extent 1,831,612 bytes
ARK ark:/87278/s6dj5hhk
Setname ir_etd
ID 191935
Reference URL https://collections.lib.utah.edu/ark:/87278/s6dj5hhk
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