PubMed · 3180770
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R J Motley, A J Reynolds. 1988. Photodermatitis from benzydamine cream.. https://doi.org/10.1111/j.1600-0536.1988.tb02875.x
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The decreased capacity of the flavin-containing monooxygenase 3 (FMO3) to oxygenate xenobiotics including trimethylamine is believed to contribute to metabolic disorders. The aim of this study was to functionally characterize FMO3 variants recently found in a Japanese population and compare them with selective functional activity of other FMO3 variants. Recombinant Glu158Lys and Glu158Lys-Glu308Gly FMO3 expressed in Escherichia coli membranes showed slightly decreased N-oxygenation of benzydamine and trimethylamine. Selective functional S-oxygenation of these variants by methyl p-tolyl sulfide or sulindac sulfide was comparable to that of wild-type FMO3. The Glu158Lys-Thr201Lys-Glu308Gly and Val257Met-Met260Val variants showed significantly decreased oxygenation of typical FMO3 substrates (i.e., approximately one-tenth of the V(max)/K(m) values). Val257Met FMO3 had a lower catalytic efficiency for methyl p-tolyl sulfide and sulindac sulfide S-oxygenation. However, compared with wild-type FMO3, Val257Met FMO3 showed a similar catalytic efficiency for N-oxygenation of benzydamine and trimethylamine. The catalytic efficiency for benzydamine and trimethylamine N-oxygenation by Arg205Cys FMO3 was only moderately decreased, but it possessed decreased sulindac sulfide S-oxygenation activity. Kinetic analysis showed that Arg205Cys FMO3 was inhibited by sulindac in a substrate-dependent manner, presumably because of selective interaction between the variant enzyme and the substrate. The results suggest that the effects of genetic variation of human FMO3 could operate at the functional level for N- and S-oxygenation for typical FMO3 substrates. Genetic polymorphism in the human FMO3 gene might lead to unexpected changes of catalytic efficiency for N- and S-oxygenation of xenobiotics and endogenous materials.
Benzydamine is a nonsteroidal anti-inflammatory drug that undergoes flavin-containing monooxygenase (FMO)-dependent metabolism to a stable N-oxide. This metabolite can be quantified with high specificity and sensitivity by using a simple reverse-phase high-performance liquid chromatography (HPLC) assay with fluorescence detection. Studies with recombinant FMO enzymes demonstrate that FMOI and FMO3 are the primary catalysts of benzydamine N-oxygenation, with minimal contributions from cytochrome P450 enzymes. Investigations conducted with human liver microsomes confirm that FMO3, in large part, is responsible for benzydamine N-oxide formation in this tissue. These features render benzydamine a useful in vitro probe for FMO activity in a wide range of tissues and cell types. In addition, benzydamine appears to be a suitable in vivo probe for human liver FMO3. This chapter provides a detailed account of the experimental protocol for determining rates of formation of benzydamine N-oxide by FMO-containing enzyme fractions.
The development and application of a flow-through amperometric biosensor for benzydamine determination in anti-inflammatory drugs is described. The biosensor was obtained by physical entrapment of monoamine oxidase in a sol-gel film applied on platinum or carbon paste conducting support. The sol-gel membranes were prepared using an optimum concentration of 3-aminopropyltriethoxy silane, 2-(3,4-epoxycyclohexyl)ethyl-trimethoxy silane, double distilled water saturated with polyethylene glycol 6000 and HCl. The developed biosensors were incorporated in a single channel flow injection system to enable the determination of benzydamine in the concentration range of 0.05-2.5 mmol l(-1) (with platinum based electrode) or within 0.1-2.5 mmol l(-1) (carbon paste based electrode). The operational stability of the bioanalytical system developed was about 3 months permitting approximately 4700 substrate measurements. The flow injection system developed enables a sampling rate of 20-25 samples h(-1) and relative S.D. of results less than 4%. The analytical usefulness of the proposed procedure was evaluated through analysis of commercial pharmaceutical products containing benzydamine, available on the Portuguese market. The results obtained did not differ significantly from the values resulting from analysis of the same products by the method described in the BP Pharmacopoeia.