The Role of Flavin-Containing Monooxygenase (FMO) in the Metabolism of Tamoxifen and Other Tertiary Amines

Abstract

Tamoxifen is utilized in breast cancer therapy and in chemoprevention. Tamoxifen may enhance risk for other neoplasias, especially endometrial cancer. The risk:benefit depends on the rate of metabolic activation versus detoxication. Cytochrome P450-dependent alpha-hydroxylation, followed by sulfonation, represents a metabolic activation pathway, producing products capable of covalent DNA adduction. In contrast, tamoxifen N-oxygenation represents a detoxication pathway, with the caveat that N-oxides can be reduced back to the parent amines. The N-oxygenation pathway will be the focus for this review. Dr. David Kupfer pioneered studies on cytochrome P450 and flavin-containing monooxygenase (FMO) tamoxifen metabolism. We collaborated with Dr. Kupfer's laboratory and recently determined that the low level of tamoxifen N-oxide production in human liver microsomes may be explained by the kinetics of FMO1 versus FMO3.

Flavin-containing monooxygenases: mutations, disease and drug response

“…Although FMO1 and FMO3 have some substrates in common, for example tamoxifen [29] and thiacetazone [30], their tissue distribution differs. Consequently, the relative contribution of a particular FMO to the metabolism of a drug will be tissue dependent.…”

Bioelectrochemical profiling of two common polymorphic variants of human FMO3 in presence of graphene oxide

“…Our data support the overall decrease in the N-oxygenation activity of the E158K polymorphic variant similar to the published literature data however, we do not observe any differences with sulindac sulfide. Furthermore, for tamoxifen metabolism only data on the E158K polymorphism has been published but we see the same improvement also in the activity of E308G [27].…”

“…As for tamoxifen N-oxygenation, Krueger and colleagues showed an improvement of both enzyme affinity and activity due to E158K mutation using a recombinant system in baculovirus [27].…”

“…These two hFMO3 variants were expressed in a recombinant system and immobilised on didodecyldimethylammonium bromide (DDAB)/GO glassy carbon electrodes and their activity tested with three hFMO3 marker drugs: benzydamine, a non-steroidal anti-inflammatory drug that is metabolised to its N-oxide by hFMO3 [15][16][17]21,25], tamoxifen, a breast cancer drug with antiestrogenic effect, also Noxygenated by hFMO3 [15][16][17]21,26,27],and sulindac sulfide, a nonsteroidal antiinflammatory drug [11] that is selectively re-oxidised to sulindac by hFMO3 S-oxygenation [2,25].…”

Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 ([7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and Its Active N-Oxide Metabolite TG100855 ([7-(2,6-Dichloro-phenyl)-5-methylbenzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine)

“…The pharmacological and toxicological importance of this metabolic pathway has been widely studied. The nitrogen-centered oxidation of tertiary amine drugs is commonly considered as a detoxification pathway resulting in nontoxic and biologically inactive metabolites (Carmella et al, 1997;Cashman and Zhang, 2006;Krueger et al, 2006). The benign nature of tertiary amine N-oxides under normal physiological conditions has been used as a prodrug approach to selectively elicit cytotoxic events associated with hypoxic conditions in solid tumor …”