Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568233
Title: Genetic variants of flavin-containing monooxygenases : consequences for drug metabolism
Author: Francois, A.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2010
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Abstract:
The metabolism of the anti-tubercular drug, thiacetazone (TAZ) by human FMOs in vitro and the disposition of TAZ in vivo in mice were studied. Reverse phase chromatography confirmed TAZ to be a substrate for human FMO1, FMO2.1 and FMO3 with the formation of TAZ-sulphinic acid and TAZ-carbodiimide via a TAZ- sulphenic acid intermediate. The products are the same as those formed by the Mycobacterium tuberculosis enzyme EtaA, the enzyme responsible for TAZ activation. Kinetic studies found FMO2.1 to be significantly more efficient at TAZ oxygenation than EtaA, FMO1 and FMO3. Asians and Europeans do not express functional FMO2 in their lungs as a result of a premature stop codon. However about 28% of African individuals lack this mutation. The products of FMO2 are expected to be toxic to mammalian cells; therefore individuals expressing FMO2 in their lungs may be at higher risk of FMO-dependent TAZ bioactivation. Protein variants of FMO3 were analysed for their ability to catalyse TAZ oxygenation. Kinetic studies showed that the L360P variant displayed a significantly higher catalytic activity towards TAZ than the wild type protein. The K158/G308 protein was inactive towards TAZ, whereas K158 or G308 variants oxygenated TAZ. These findings may reflect the underlying mechanism of TAZ-dependent liver toxicity reported in patients taking TAZ as part of treatment for TB. Mouse liver and lung microsome experiments indicated that both FMOs and cytochromes P450 (CYPs) metabolise TAZ in vitro. FMO contribution was higher in the lung than the liver. Kinetic studies using microsomes from Fmo1 knockout mice show FMO1 to be the predominant contributor to TAZ oxygenation in vitro. Metabolism of TAZ in liver and lungs of mice in vivo was not observed, however TAZ, TAZ-sulphenic acid, TAZ-sulphinic acid and TAZ-carbodiimide were identified in kidney.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.568233  DOI: Not available
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