Pyrrolizidine alkaloids metabolic activation

Lin G, Cui Y-Y, Liu X-Q and Wang Z-T (2002b), Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloids clivorine , Chem Res Toxicol, 15, 1421-1428. 

Monocrotaline (170) has been the subject of extensive metabolic study with mammalian and microbiological systems. Pyrrolizidine alkaloids such as monocrotaline require metabolic activation to the corresponding pyrrole derivatives or dehydro alkaloids before they are capable of forming covalent bonds with critical macromolecules within the cell. The X-ray structure of dehydromonocrotaline has recently been determined (226), and the ability of dihydroretronicine derived from monocrotaline to react with deoxyguanosine has been demonstrated in vitro (225). 

Figure 2.12 Metabolic activation by the liver of pyrrolizidine alkaloid to the toxic pyrrole (liver bound and highly toxic) and the glutathione conjugate (excretion metabolite).

Ornithine is a metabolically quite active amino acid, and the important precursor of pyrrolidine nucleus, which is found in pyrrolizidine alkaloids. Ornithine itself is a non-protein amino acid formed mainly from L-glumate in plants, and synthesized from the urea cycle in animals as a result of the reaction catalyzed by enzymes in arginine. 

There exists evidence that some insects store dietary alkaloids derived from natural sources. Figure 98 presents insect species that are known to accumulate pyrrolizidine alkaloids during different developmental stages. The larvae and adults of these insects can metabolize pyrrolizidine alkaloids in current physiological activities. These alkaloids are not toxic for these organisms. Moreover, there is observed trace accumulation of a portion of these compounds in the liver. There is no definitive purpose for these traces. Generally, the opinion presented in 1888 by Stahl in Germany that the accumulation of alkaloids is for defensive purposes has been most often cited in the research literature. 

Figure 6.7 The structure of the pyrrolizidine alkaloid monocrotaline and the microsomal enzyme-mediated metabolic activation of the pyrrolizidine alkaloid nucleus.

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Many pyrrolizidine alkaloids are metabolized to toxic pyrrole metabolites in the liver by mixed-function oxidases. The structural and chemical features necessary for the formation of these metabolites have been discussed.77 The most important features, in addition to the 3-hydroxymethyl-3-pyrroline system, are steric hindrance to hydrolysis of the ester, lipophilic character (favouring attack by the hepatic microsomal enzymes), and the presence of a conformation that allows preferential oxidation of the pyrroline ring rather than 7V-oxidation. The alkylating activities of a series of these pyrrole derivatives have been examined.78... 

Both liver and kidney systems are affected by a variety of secondary metabolites, and the pyrrolizidine alkaloids have been discussed earlier (Tables IV and V). The alkaloids are activated during the detoxification process, and this can lead to liver cancer. Also, many other enzyme or metabolic inhibitors (e.g., amanitine), discussed previously, are liver toxins. 

Mattocks has reviewed the metabolic activation of pyrrolizidine alkaloids. Schoen-taP has amplified her hypothesis that the acute effects of pyrrolizidine alkaloid toxidty are due to the alkylation of coenzymes. A summary of the physiological activity and biosynthesis of the pyrrolizidine alkaloids has appeared. ... 

An excellent volume on the pyrrolizidine alkaloids has recently been published. The chemistry of these alkaloids is briefly discussed, but considerable emphasis is placed on their pharmacology and pathogenicity. In another reference, Culvenor and his collaborators discuss the hepatotoxicity, antimitotic properties, and the metabolism of these alkaloids. The significance of the alkylating properties in relation to the antimitotic activity, and the role of pyrroles formed in vivo, are also discussed. 

Apart from the chemistry of these pyrrolizidine alkaloids, their physiological effects, in particular their hepatotoxicity, have been investigated in depth by the CSIRO Division of Animal Health, as a result of which it has been possible to establish correlations between activity and structure liver damage is caused by alkaloids such as 90 or 91 because unsaturated amino alcohols of this type, which are esterified on one or both hydroxyl groups, undergo metabolism in the liver to form the toxin 93 this substance is immediately responsible for the mutagenic and carcinogenic effects observed [106, 107], which include... 

There is evidence that some insects store dietary alkaloids derived from natural sources. Figure 4.3 presents insect species that are known to accumulate pyrrolizidine alkaloids during different developmental stages. The larvae and adults of these insects can metabolize pyrrolizidine alkaloids in current physiological activities. These alkaloids are not toxic for these organisms. 

Most pyrrolizidine alkaloids are esters of basic alcohols known as necine bases. The most frequently studied pyrrolizidine alkaloids are formed from the polyamines, putrescine and spermidine, and possess one of three common necine bases retronecine, heliotridine, and otonecine. Putrescine is utilized exclusively as a substrate in secondary metabolism, whereas spermidine is a universal cell-growth factor involved in many physiological processes in eukaryotes. Spermidine biosynthesis begins with the decarboxylation of SAM by SAM decarboxylase 165). The aminopropyl group is then transferred from decarboxylated SAM to putrescine by spermidine synthase to form spermidine (Scheme 5). Putrescine can be produced from ornithine by ODC. However, putrescine is derived from the arginine-agmatine pathway in pyrrolizidine alkaloid-producing plants due to the absence of ODC activity 166). 

Wang Y-P, Yan J, Fu PP, Chou MW (2005) Metabolic activation of the tumorigenic pyrrolizidine alkaloid, retrorsine, leading to DNA adduct formation in vivo. Int J Environ Res Public Health 2 74-79... 

Fu PP, Xia Q, Lin G (2004) Pyrrolizidine alkaloids - genotoxicity, metabolism enzymes, metabolic activation, and mechanism. Drug Metab Revs 36 1-55... 

Xia Q, Chou MW, Edgar JA, Doerge DR, Fu PP (2006) Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine. Cancer Lett 231 138-145... 

A toxin is activated in the liver, and then carried by die blood to die lung. For example, pyrrolizidine alkaloids are metabolized to reactive pyrrole metabolites in the liver they then bind to both liver and lung cells. 

Fig. 16.2 Pyrrolizidine alkaloid (PA) biosynthesis and posttranslational activation of eIF5A. a Homospermidine synthase (HSS) begins PA biosynthesis by forming homospermidine, the first pathway-specific intermediate, which is further metabolized and eventually incorporated into the necine base of PAs. As an example, the generation of senecionine A-oxide is shown, b In the first of two reactions involved in posttranslational activation of the elFSA protein, deoxyhupsine synthase (DHS) catalyzes a reaction analogous to that of HSS...

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