Pyrrolizidine toxicity

A dietary supplement may be safe when taken in the recommended doses but may become dangerous in higher doses. However, patients may develop side effects even when ingesting recommended doses. Adverse reactions may be due to allergic reactions, dietary supplements containing toxic substances, mis-identification of plant, mislabeling of plant, natural toxic substances such as pyrrolizidine alkaloids in comfrey, unnatural toxic substances such as heavy metals, or pesticides. 

Extensive metabolic work continues with the pyrrolizidine alkaloids many of which are known toxic principles of plants responsible for conditions such as irreversible hemorrhagic liver necrosis, megalocytosis, and cancer. Considerable interest remains in the metabolism of pyrrolizidine alkaloids and their A-oxides to metabolic pyrroles thought to participate in molecular events associated with the above-mentioned toxicities. The chemistry and pharmacological properties of the pyrrolizidine alkaloids is authoritatively discussed by Wrobel in Volume 26 of this treatise. 

Indicine IV-oxide (169) (Scheme 36) is a clinically important pyrrolizidine alkaloid being used in the treatment of neoplasms. The compound is an attractive drug candidate because it does not have the acute toxicity observed in other pyrrolizidine alkaloids. Indicine IV-oxide apparently demonstrates increased biological activity and toxicity after reduction to the tertiary amine. Duffel and Gillespie (90) demonstrated that horseradish peroxidase catalyzes the reduction of indicine IV-oxide to indicine in an anaerobic reaction requiring a reduced pyridine nucleotide (either NADH or NADPH) and a flavin coenzyme (FMN or FAD). Rat liver microsomes and the 100,000 x g supernatant fraction also catalyze the reduction of the IV-oxide, and cofactor requirements and inhibition characteristics with these enzyme systems are similar to those exhibited by horseradish peroxidase. Sodium azide inhibited the TV-oxide reduction reaction, while aminotriazole did not. With rat liver microsomes, IV-octylamine decreased... 

Griffin, D.S., and SegaU, H.J., 1987, Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans-4-OH-2-hexenal,... 

Figure 2.11 Pyrrolizidine alkaloid toxins including (a) the pyrrolizidine nucleus, (b) retronecine, a less toxic monoester, and (c) jacobine, a highly toxic cyclic diester.

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).

Huxtable, R.J. and Cooper, R.A. (2000). Pyrrolizidine alkaloids physicochemical correlates of metabolism and toxicity, in Tu, A.T. and Gaffield W., Eds., Natural and selected synthetic toxins biological implications, American Chemical Society, Washington, D.C., pp. 100-117. 

McLean AEM. 1970. The effect of protein deficiency and microsomal enzyme induction by DDT and phenobarbitone on the acute toxicity of chloroform and a pyrrolizidine alkaloid, retrorsine. Br J Exp Pathol 51 317-321. 

Because 1,4-dichlorobenzene is a liver toxin, it probably can interact with other chemicals that are liver toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc ), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or S5mergistic effects. 

At overwintering sites of the monarch butterfly [Danaus plexippus) in Mexico, only one of the three local mouse species, Peromyscus melanotis, actually feeds on the butterflies. The monarchs contain cardiac glycosides (CG) and pyrrolizidine alkaloids (PA). All three species of mice have similarly low avoidance thresholds to PA (specifically, monocrotaline). But P. melanotis is less sensitive to CG (specifically, digitoxin) than the other two, Reithrodontomys sumichrasti and Peromyscus aztecus. Laboratory tests indicate that PA is toxic to young mice. 

Quinolizidine alkaloids are non-toxic to the legumes which produce them. On the other hand, the quinolizidine alkaloids can be toxic and in some cases very toxic to other organisms. The biotoxicity of alkaloids has for some time been considered to be connected with their bitter taste" ° ". The quinolizidine alkaloids are certainly bitter in taste to humans. However, not all alkaloids are. Literature states that some pyrrolizidine and indolizidine alkaloids are not bitter in their pure forms" Furthermore, there are many non-alkaloid compounds, such as flavonoids, that are bitter in taste but non-toxic. Therefore, although quinolizidine alkaloids are bitter, the connection between biotoxicity and bitter taste is not absolute. 

Figure 89. Acute toxicity (LD50) of some pyrrolizidine alkaloids in male rats. (Sources Refs [472, 473, 474, 475]).

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. 

White, I. N. H., Mattocks, A. R. and Butler, W. H. 1973. The conversion of the pyrrolizidine alkaloid retrorsine to pyrrolic derivatives in vivo and in vitro and its acute toxicity to various animal species. Chemistry-Biology Interaction, 6 207-218. 

McLean, E. K. 1970. The toxic actions of pyrrolizidine (Senecio) alkaloids. Pharmacological Review, 22 429 83. 

Acute toxicity of berberine and thebaine Acute toxicity of some quinolizidine alkaloids Acute toxicity of some pyrrolizidine alkaloids Some narcotics and their derivatives. 

Herbs rich in toxic pyrrolizidine alkaloids Cape aloesf... 

Some natural products, or their degradation products, represent a hazard for mammals not because of general toxicity but for subtle, adverse properties, such as carcinogenicity and tumor promotion. They are best known fi om marine dinoflagellates (okadaic acid and structural analogues), filamentous fungi (trichothecenes and ochratoxins), and plants (pyrrolizidine alkaloids). 

Alkaloids are basic plant natural products that typically have a nitrogen atom as part of a heterocyclic ring system and indeed are classified on this basis. Thus major classes of alkaloids are based on indole, isoquinoline, pyrrolidine, piperidine, pyrrolizidine, quinoline, tropane, quinolizidine or other heterocyclic ring systems. Other alkaloids are basic monoterpenoid, sesquiterpenoid, diterpenoid, steroid, purine, pyrimidine or peptide entities. Some of these compounds are exceptionally toxic [1,6, 7-12]. 

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... 

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