J. E. Peterson

Hepato- and pneumotoxicity of pyrrolizidine alkaloids and derivatives in relation to molecular structure.

62 pyrrolizidine alkaloids and derivatives have been screened for acute and chronic hepato- and pneumotoxicity by the single dose method previously described. This procedure is satisfactory for the compounds of medium to high hepatotoxicity but failed to detect toxicity in certain other compounds of known, low hepatotoxicity. New findings significant in relation to hepatotoxicity are as follows: (i) On a molar basis, diesters of heliotridine and retronecine are about 4 times as toxic as the respective mono-esters and heliotridine esters are 2-4 times as toxic as retronecine esters. (ii) Crotanecine esters are less toxic than retronecine esters, and the 6,9-diester madurensine, 2-4 times less toxic than the 7,9-diester anacrotine (the difference being ascribed to there being only one reactive alkylating centre in the toxic metabolite from madurensine). (iii) Hepatotoxicity was confirmed for 7-angelylheliotridine but not observed for 9-angelyheliotridine and 7- and 9-angelylretronecine. (iv) Other significant compounds failing to induce hepatotoxicity were 9-pivalyl- and 7,9-dipivalyheliotridine, the alpha- and beta-epoxides of monocrotaline, 7-angelyl-1-methylenepyrrolizidine and the methiodides of monocrotaline and senecionine. The following compounds are readily converted by rat liver microsomes in vitro into dehydroheliotridine (or dehydroretronecine): 7- and 9-angelyheliotridine, 7- and 9-angelylretronecine, 7,9-dipivalylheliotridine and otosenine. 7,9-Divalerylheliotridine, the alpha- and beta-epoxides of monocrotaline, and retusamine yield pyrrolic metabolites more slowly. The preparation and characterisation of several alkaloid derivatives are described. Chronic lung lesions were produced by most compounds which gave chronic liver lesions, although a higher dose was required in some instances. This requirement may sometimes mean that chronic lung lesions cannot be induced because of the intervention of acute or peracute deaths. Apart from this factor, structure activity requirements for pneumotoxicity are the same as for hepatotoxicity, consistent with their being both caused by the same toxic metabolites.

Inhibition of glycosylation by corynetoxin, the causative agent of annual ryegrass toxicity: A comparison with tunicamycin

The biological activities of corynetoxins, the causative agents of annual ryegrass toxicity, were compared with those of the closely related tunicamycins and found to be essentially identical. Both showed similar antibiotic activity against Newcastle disease virus and a range of gram-positive bacteria. In preparations of rat liver rough microsomes they also strongly inhibited the uridine diphospho-N-acetylglucosamine (UDP-GlcNAc):dolichol-P N-acetylglucosamine-1-phosphate (GlcNAc-1-P) transferase, an enzyme essential for N-glycosylation of glycoproteins. Pretreatment of rats with corynetoxins resulted in dose- and time-related reduction in the level of activity of this transferase in liver microsomal preparations. The implications of this reduction are discussed with reference to annual ryegrass toxicity, the only field disease known to be caused by tunicamycin-related compounds. Both corynetoxin and tunicamycin produced similar neurological effects and increased vascular permeability in nursling rats and they showed similar LD50-values of 137 and 132 micrograms/kg, respectively, in the nursling rats.

Structure and toxicity of the alkaloids of Russian comfrey ( Symphytum x uplandicum Nyman), a medicinal herb and item of human diet

Eight pyrrolizidine alkaloids of hepatotoxic type have been indentified in leaves ofSymphytum × uplandicum The combined alkaloids exhibit chronic hepatotoxicity in rats.

Permanent testicular damage induced in rats by a single dose of tunicamycin

Tunicamycin administered as a single subcutaneous dose of 200 micrograms/kg caused permanent destruction of seminiferous tubules in adult male rats. The fertility of females was unimpaired by doses of up to 450 micrograms/kg. Degenerative changes in seminiferous tubule epithelium commenced 3 to 5 days after injection and by day 19 affected 95% of tubule profiles in sections. In 95% of tubules only Sertoli cells survived to day 56. Tubules without any surviving cells were present from day 19 and slowly increased in number, a variable proportion becoming mineralised. No regeneration occurred within one year. Leydig cells became more prominent because of the atrophy of seminiferous tubules, but their total mass did not differ significantly from that of control rats, nor did the plasma concentration of testosterone. Changes in tissues other than the tests were transient. The testicular damage seems to have resulted from localised ischaemia caused by tunicamycin-induced vasoconstriction.

Biliary hyperplasia and carcinogenesis in chronic liver damage induced in rats by phomopsin

&NA; Phomopsin, a hexapeptide mycotoxin contaminant of lupin plant and seed materials, was administered subcutaneously to adult rats at a daily dose rate of 30 μg/kg body weight (approximately 0.005 median lethal dose) for 2, 6 or 17 wks and the development of liver damage was observed during treatment and for up to 2 yr after. All rats injected for 17 wks developed permanent liver damage characterized by nodular cirrhosis and extensive biliary hyperplasia. Cholangiomas developed in 60% of these rats and cholangiocarcinomas and hepatocellular carcinomas in 13%. Similar effects were produced in some rats injected for 6 wks, while in others the cessation of treatment was followed by almost complete regression of the liver lesions. Livers damaged by 2 wks of injection had fully recovered within a few wks. The permanence of the liver damage is relevant to the management of stock exposed seasonally to the toxin, while its carcinogenic potential in rats, although not high, indicates the need for monitoring of the phomopsin content of lupin seed or flour prepared for human consumption.