Date of Award

2002

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

David McMillan

Second Advisor

Thomas Walle

Third Advisor

Brad Schulte

Fourth Advisor

Robert Means

Fifth Advisor

David Jollow

Abstract

Primaquine is an important antimalarial drug that is often dose-limited in therapy by the onset of hemolytic anemia. It is well accepted that this toxicity is due to the action of its metabolites and not the parent compound. However, the toxic species have not been identified and little is known about the mechanism underlying primaquine-induced red cell injury. Previous studies to identify the hemotoxic metabolites have focused on the redox active phenolic derivatives of primaquine and have shown that a number of these compounds are capable of decreasing red cell GSH levels and oxidizing oxyhemoglobin to methemoglobin. However, these derivatives have not been detected in humans following primaquine administration. Since N-hydroxy metabolites are known to mediate the hemotoxicity of several other arylamines, this dissertation addresses the possibility that an N hydroxy metabolite of primaquine may play a role in the hemotoxicity of the parent compound. Metabolic studies in rat and human microsomes determined that the known human primaquine metabolite, 6-methoxy-8-aminoquinoline (6-MAQ) is N-hydroxylated to 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH). MAQ-NOH was shown to be hemolytic in vivo in rats, and directly hemotoxic in rat erythrocytes. These observations suggest that primaquine can be metabolized to MAQ-NOH and that this metabolite has the requisite properties to play a role in the hemotoxicity of the parent compound. In regard to the mechanism underlying MAQ-NOH hemolytic activity, it was demonstrated that under hemolytic conditions, MAQ-NOH induced an oxidative stress within red cells, but the pattern of responses was quite different than other N-hydroxylamines previously shown to have direct hemolytic activity. In this dissertation, data is presented to suggest that MAQ-NOH may induce hemolytic injury in the red cell by more than one mechanism; one that involves lipid peroxidation in the presence of normal amounts of erythrocytic GSH, and one that involves protein oxidation in red cells with low levels of GSH, as seen in individuals with glucose-6-phosphate dehydrogenase deficiency. The relative contribution of MAQ-NOH versus the phenolic type derivatives in mediating this toxicity remains to be assessed.

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