ISSN:
1432-1912
Keywords:
Monoamine Oxidase
;
MAO Inhibitors
;
Nitrofurans
;
Hydrazines
;
Enzyme Inhibition (Irreversible)
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary Four bacteriostatically active nitrofurfurylidene compounds and their respective hydrazine moieties were administered to male Wistar rats. MAO activity was measured in vivo by different methods in liver, brain, and small intestine. Inhibition of DAO activity was determined in small intestine of rats and, in in-vitro experiments, in a partially purified pig kidney enzyme preparation. 1. Only those nitrofuran derivatives, which contain a hydrazine moiety that also inhibited the enzyme, were MAO inhibitors. The same was true for DAO; both enzymes were inhibited irreversibly. It is concluded that a hydrazine derivative with a free NH2-group as produced by metabolic transformation of the parent compound must be responsible for the amine oxidase inhibiting action of nitrofuran derivatives in vivo. Thus, both N-(5-nitro-2-furfurylidene)-3-amino-2-oxazolidinone and 3-amino-2-oxazolidinone were MAO inhibitors, the latter being 30–60 times more potent. K-(5-nitro-2-furfurylidene)-3-amino-5-methylmercaptomethyl-2-oxazolidinone was not an MAO inhibitor, although 3-amino-5-methylmercaptomethyl-2-oxazolidinone did inhibit the enzyme. In this case, the parent compound is possibly not metabolized to an active substance. In regard to 5-nitro-2-furfurylidene-4-hydroxybenzoyl-hydrazide and N-(5-nitro-2-furfurylidene)-1-amino-hydantoin, both the parent compounds and their respective hydrazine moieties-4-hydroxybenzoyl-hydrazide and 1-amino-hydantoin-were not inhibitors of MAO. 2. The steepness of the dose-response curves of MAO inhibition decreased in the order brain-liver-small intestine. These differences are explained by different turnover rates of enzyme protein as reflected by different half-life times of enzyme reactivation in the respective organs (10, 3, and 1.8 days for brain, liver, and small intestine, respectively). Consequently, duration and also degree of an irreversible MAO inhibition depend not only on the local concentration of the inhibiting drug, but also on the rate of protein turnover in the respective organ. It is stated that, inter alia, accordance between enzyme reactivation rate and enzyme protein turnover rate is a criterion for an irreversible MAO inhibitor.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00997076
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