Alkaloids mammalian toxicity

Since some alkaloids exhibit great mammalian toxicity (e.g., batrachotoxin, samandarine), it is obvious that these compounds are capable of initiating severe biochemical and physiological lesions. However, it should not be overlooked that toxicological evaluations of most alkaloids have been implemented by in vitro studies in which the alkaloids have been introduced subcutaneously. On the other hand, in nature, in the absence of a venom apparatus, these compounds would be... 

The enormous number and structural variety of plant alkaloids would lead one to expect them to be a rich hunting ground for antifeedants. Nevertheless, they seem to be relatively neglected compared to other groups. Their often high mammalian toxicity may be the reason. 

Nicotine, an alkaloid, is extracted from leaves of tobacco plants (Nicotiana tabacum and Nic-otiana rustica). It is used in home gardens and greenhouses for control of sucking insects such as leafhoppers, aphids, scales, thrips, and whiteflies. However, the use of nicotine is rapidly declining and is being replaced by newer synthetic insecticides because of its comparatively high mammalian toxicity. Its oral LD50 in rats is 55 mg/kg. 

Alkaloids in mixtures extracted from plants have been known since ancient times. They usually have some form of biological activity, which can range from high mammalian toxicity to valuable therapeutic properties of many different kinds. Mention will be made in Section 3.2.1.3 of some of these biological properties. 

Metabolism of saturated pyrrolizidine alkaloids (necic acid esters of platynecine, hastanecine, rosmarinecine and isoretronecanol (Fig. 13.1)) by mammals has not yet been extensively studied, in part because the saturated ester alkaloids and their necines do not display mammalian toxicity. 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Over 40 norditerpenoid alkaloids have been reported in species of larkspurs. Data on toxicity in a mammalian system have been reported for 25 of these by the Poisonous Plant Research Laboratory (reviewed in Panter et ah, 2002). The commonality among all the wild larkspur species is the presence of norditerpenoid alkaloids, which are responsible for poisoning livestock. 

Many pyrrolizidine alkaloids are known to produce pronounced hepatic toxicity and there are many recorded cases of livestock poisoning. Potentially toxic structures have 1,2-unsaturation in the pyrrolizidine ring and an ester function on the side-chain. Although themselves non-toxic, these alkaloids are transformed by mammalian liver... 

The toxicity of plants that contain pyrrolizidine alkaloids has been discussed in an earlier volume of this series (163), and the relationship between the toxic nature of the plants and the metabolism of their alkaloids by the victim has been reviewed (164). Since the toxicity of the pyrrolizidine alkaloids in mammals seems to be due to their metabolites rather than to the alkaloids themselves (164), considerable effort has been expended in the identification of the metabolites produced both in vivo and in vitro by mammalian systems. The material summarized in Table V (165-172) is supplementary to that discussed in reference 164. 

The antimicrobial activity of aporphine alkaloids in general has been tested and oxoaporphines were the most active [108]. Some of these alkaloids are found to be toxic for mammalian cells in tissue cultures [109]. In another study of antimicrobial activity of fourteen benzylisoquinoline alkaloids, two oxoaporphines isolated from species of South American Menispermaceae, lysicamine (10) and O-methylmoschatoline (homomoschatoline) (11), had activity against cocci and gram positive bacilli, including Mycobacterium phlei [110]. 

Emetine (Fig. 7-9) in the form of the crude drug obtained from the roots and rhizomes of Ipecac (Cephaelis ipecacuanha) has been in use since the seventeenth century. The alkaloid, as the hydrochloride, has been used parenterally to treat amebic dysentery. It is also effective in hepatic infestation, but not against amebic cysts. Because of its cardiac toxicity and emetogenic properties, it has been superseded by metronidazole and chloroquine, but it is still used as an alternative. The amebicidal mechanism of emetine is protein synthesis inhibition by interference of peptidyl-RNA translocation. Since this action is general to eukaryotic cells, its relative selectivity in the presence of mammalian cells is not well understood. Unrelated uses of Ipecac (presumably due to its alkaloid content) are as an expectorant in cough preparations and an emergency emetic (Syrup of Ipecac). 

Quinoline compounds and the plants that contain them have historically anchored the antimalarial arsenal, and they remain principal drugs today. Quinine and its diastereomer, quinidine, are quinoline alkaloids which were isolated in 1820 from the bark of the Cinchona tree, by virtue of the traditional South American use of this bark to treat intermittent fevers. Quinine is an effective schizonticide (i.e., it kills the form of the parasite in peripheral blood), but because it also affects mammalian lysosomes, the drug has been associated with significant adverse toxicity (48,50). The development of synthetic derivatives of quinine has resulted in improvement in potency and selectivity over the parent compound. Chloroquine and mefloquine are more potent and less toxic than quinine (49,51), thus, chloroquine had largely replaced quinine in clinical use however, resistance of P. falciparum to chloroquine has been reported... 

Similarly it has been shown that the most potent norditerpenoid alkaloids acting as inhibitors of mammalian and insect cholinergic receptors have the C-l 8 anthranilic acid esterification, characteristic of the Delphinium norditerpenoid alkaloid methyllycaconitine (MLA), structurally-related to aconitine [40-42], MLA also had antifeedant effects against Spodoptera eridania with associated post-ingestive and toxic effects at doses within the effective antifeedant dose range of compound 30 [40], suggesting a similar antifeedant mode of action between MLA/aconitine and the C-20 diterpenoid alkaloids. 

Tavares, D.C., and C.S. Takahashi. 1994. Evaluation of the geno-toxic potential of the alkaloid boldine in mammalian cell systems in vitro and in vivo. Mutat. Res. 321 (3) 139-145. 

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