Pyrrolizidine alkaloids acute

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... 

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. 

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

Mattocks, A. R. 1972. Acute hepatoxicity and pyrrolic metabolities in rats dosed with pyrrolizidine alkaloids. Chemistry-Biology Interaction, 5 227-242. 

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. 

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

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. 

The effects of pyrrolizidine alkaloids on the mixed-function oxidase enzyme system in rat liver have been studied.79,80 Dehydroheliotridine and heliotrine (at higher dose rates) have similar effects on pregnant rats and their embryos.81 The development of pulmonary hypertension and obstructive lesions in rats after administration of monocrotaline (48) has been studied.82 Butylated hydroxyanisole protects young mice against the acute toxicity of monocrotaline.83 Reduced levels of pyrrole metabolites were observed. 

Veno-occlusive disease (VOD) differs from Budd-Chiari syndrome in that it consists of occlusive fibrosis of the small intrahepatic veins. VOD may present as either an acute form with sudden ascites, liver enlargement and rapidly rising bilirubin, or as a chronic form with fibrosis and cirrhosis. One of the main causes of VOD is the use of cyclophosphamide or alkalating agents during conditioning for bone marrow transplantation, where it occurs in up to 20% of cases. Other causes include irradiation, antineoplastic drugs, pyrrolizidine alkaloids and alcohol. 

Mattocks, A.R. (1972) Acute hepatotoxicity and pyrrolic metabolites in rats dosed with pyrrolizidine alkaloids. Chem. Biol. Interact., 5, 227-42. 

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. ... 

Cases of acute hepatitis linked to the use of Jin Bu Huan are less clear, because adulteration with levo-tetrahydropalmatine, an alkaloid present in Stephania and Corydalis, has been implicated (Brent, 1998 Woolf et al., 1994). Similarly, adulteration may be the cause of a fatal case of VOD attributed to skullcap (Scutellaria lateriflora), because this plant does not contain pyrrolizidine alkaloids associated with this syndrome. Nonetheless, in one instance, skullcap was implicated in a case of mild flulike symptoms associated with jaundice and abnormal liver function test results (Enlow, 1996). 

Figure 3. Correlation of calculated log P (octanol/water) values with acute morbidity of pyrrolizidine alkaloids. Structures of two oudying compounds are shown.

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