Physiological And Biochemical Targets For Alkaloids

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 introduced into the body of a vertebrate through oral administration. Thus, rejection. can reflect noxious or toxic effects on nerves and muscles of buccal tissue before alkaloids reach the intestine as a prelude to absorption into the circulatory system. It can be anticipated that toxicological differences may reflect the mode of introduction of toxic alkaloids into the body of a vertebrate. For example, the response to caffeine in laboratory studies with rats demonstrated that toxicity patterns were pronounced with bolus oral doses by intubation, whereas administration of the alkaloid in the drinking water did not result in any of the expressions of toxicity encountered with intubation.13 However, this consideration notwithstanding, diverse studies with a variety of alkaloids have demonstrated unambiguously that these compounds perturb many physiological and biochemical systems as agents of pronounced toxicity. A brief examination of alkaloids as selective toxins emphasizes the many roles that these compounds play as deterrents.

Wink37 has identified a considerable diversity of cellular targets that are vulnerable to the cytotoxic effects of various alkaloids. Although some of these data have been obtained. by screening these natural products as anticancer agents, there are no grounds for believing that the susceptibility of a cancer cell and a "normal" cell will be somewhat similar. Since herbivores would be characterized by "normal" cells, the production of allelochemical alkaloids by plants can be regarded as a powerful deterrent for herbivores.

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization

Some alkaloids interfere with the assembly of microtubules (taxol, colchicine, maytansine), inhibit key enzymes such as adenylate cyclase (papaverine, theophylline, theobromine), activate neuromuscular systems involving ACH (physostigmine, coniine, nicotine), inhibit digestive processes (emetine, lobeline, morphine), modulate liver and kidney function (pyrrolizidine alkaloids, amanitine), and destabilize the blood and circulatory system (vinblastine, colchicine).

These results, while requiring considerable in vitro extension, document the fact that a variety of alkaloids are capable of inhibiting central processes at different levels (organismic, organ, cellular), thus causing serious biochemical and physiological lesions. Although the chemistry of these compounds and their detailed modes of action are far from complete, the results as presented clearly show that these nitrogen heterocycles are structural and pharmacological "gold mines" that ultimately affect animals significantly and often deleteriously. It would be no exaggeration to state for alkaloid researchers, "The best is yet to come."

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