The use of ethionamide has been increasing in drug regiments due to greater incidence of multidrug resistance tuberculosis around the world. Ethionamide is metabolized into antimicrobial relevant compounds by different flavin-containing monooxygenase (FMO) enzymes including FMO1, FMO2, and FMO3. FMOs are found in various locations in the body including the intestine, kidney, liver, and lung. In humans, active functional FMO2*1 is found in approximately 50% of Sub-Saharan Africans and a truncated, inactive FMO2*2, is found in all Caucasians and Asians. Polymorphisms in human FMO2 were investigated by comparing differences in metabolism of ethionamide in wildtype mice relative to Fmo 1/2/4 null mice. All mice were capable of metabolizing ethionamide into ethionamide S-oxide and 2-ethyl-4-amidopyridine. Wildtype mice had higher plasma levels of metabolites than parent compound. In contrast, Fmo 1/2/4 null mice had higher plasma levels of parent compound than metabolites. In both mouse populations, maximum ethionamide concentration peaked at 2 hours post-exposure. Increased metabolism of ethionamide in wildtype mice may deplete glutathione pools and induce oxidative stress leading to greater toxicity and adverse drug effects. This murine model is used to demonstrate the polymorphic differences of FMO2 occurring in humans. Taking these differences into account, polymorphisms of drug metabolizing enzymes provide a basis for increasing specific and individualized drug treatment regiments in susceptible populations. / Graduation date: 2012
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/28607 |
| Date | 22 March 2012 |
| Creators | Palmer, Amy L. (Amy Leigh) |
| Contributors | Williams, David E. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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