Metabolism of acridine by rat-liver enzymes.

Metabolism of acridine by S10 fractions from control adult male Sprague-Dawley rats produces mainly 9- acridone , apparently catalyzed by aldehyde oxidase ( ED1 .2.3.1). In contrast, the predominant metabolic product produced by the corresponding S10 fraction of PCB-induced liver enzymes is a dihydrodiol (either the 2,3- or 3,4-isomer) presumably derived from an epoxide. Several minor metabolites of unknown structure are also formed. During in vitro reactions aldehyde oxidase requires neither atmospheric oxygen nor NADPH. Acridine has been reported to be mutagenic to Salmonella typhimurium, but only in the absence of PCB-induced activating enzymes. It also has been reported to produce chromosomal aberrations in cultured Chinese hamster cells both with and without enzymatic activation. While a connection between aldehyde oxidase catalysis and mutagenic action of acridine has not been established, the extensive metabolic potential of this compound implies that complete description of mutagenicity will be difficult.

Isoquinoline alkaloids. Inhibitory actions on cation-dependent ATP-phosphohydrolases.

Representatives of eleven different classes of isoquinoline alkaloids inhibit Na+, K+-ATPase and Mg2+-ATPase in rat brain microsomal preparations. In most cases the Na+, K+-ATPase is more sensitive than Mg2+-ATPase to inhibition by the alkaloids. The classes of alkaloids can be ranked according to potency of inhibition of Na+, K+-ATPase. Protoberberines are most effective, followed in decreasing order by benzophenanthridines, benzylisoquinolines, aporphines, tetrahydroprotoberberines, pavines, protopines, isoquinolines, tetrahydrobenzylisoquinolines, morphinanes, and tetrahydroisoquinolines. As specific representatives of each of the first four classes of alkaloids, berberine, sanguinarine, papaveroline and 1,2,10,11-tetrahydroxyaporphine, respectively, prove most valuable in kinetic studies because they exhibit the greatest inhibitory action on brain Na+, K+-ATPase. Kinetic analyses plotted in double reciprocal form reveal that berberine and 1,2,10,11-tetrahydroxyaporphine are simple linear competitive inhibitors with respect to ATP, whereas sanguinarine and papaveroline are simple linear noncompetitive inhibitors. These four representative alkaloids exhibit non-linear competitive inhibition with respect to Na+-activation. Additionally, these alkaloids significantly inhibit rat brain microsomal K+-activated pNPPase. The results demonstrate that certain members of several classes of isoquinoline alkaloids markedly affect various cation-dependent phosphohydrolases in vitro.

Disposition of catecholamine-derived alkaloids in mammalian systems.

Tetrahydropapaveroline, the tetrahydroisoquinoline alkaloid derived from dopamine, is converted in vivo by rats and by rat liver and brain preparations to tetrahydroprotoberberine alkaloids. The latter alkaloids have also been identified for the first time in the urine of parkinsonian patients receiving L-dopa therapy. These findings suggest that man, like plants, may have the ability to elaborate several classes of alkaloids with potentially important pharmacological consequences. Thus, this newly demonstrated ability of mammalian systems to evoke the biosynthesis of benzyl-tetrahydroisoquinoline-derived alkaloids - a capability previously considered unique to plants - elects the tetrahydroprotoberberine alkaloids as representative of the first class of a possible constellation of complex mammalian alkaloids elaborated from the neuroamines.