- The metabolism of pyrrolizidine alkaloids and other
drugs was studied with regard to nutritional status and
species differences. Pyrrolizidine alkaloids which are biotransformed
to severely toxic metabolites were isolated
from tansy ragwort (Senecio jacobaea). Semi-purified alkaloid
crystals containing five alkaloids (senecionine, seneciophylline,
jacobine, jacoline, and jacozine) were prepared
and found to be free of N-oxide and dihydropyrrolizidine
Liver changes occurring with time resulting from a
single administration (i.p.) of the alkaloidal preparation
were studied. Of the mixed-function oxidases, alkaloid dehydrogenase
was inhibited immediately (one hour) and recovered
slowly. Inhibition coincided well with levels of
liver bound pyrrole. On the other hand, cytochrome P-450,
N-demethylase, and microsomal protein all were significantly
depressed after one day but were normal by six days.
N-demethylase activity was significantly elevated and liver pyrrole negligible by 57 days. A transient enlargement
(six days) of the spleen was also observed. In a second
experiment, one hour after a subacute dose of alkaloid,
liver sulfhydryls were mildly depleted.
A wide range of alkaloid dehydrogenase activities in
different species was demonstrated. Nonogastric herbivores
(4amster and rabbit) were highest followed by monogastric
species (mouse and rat), ruminant species (cattle and
sheep), and avian species (chickens and Japanese quail).
With the exception of rabbits and chickens, pyrrole production
in vitro generally correlates to the susceptibility of
the species resulting from the fed plant.
Chronic administration (12 days) of excess levels of
selenium, copper, and vitamin A was studied using rats.
High selenium caused a significant increase in liver weight,
but had no effect on microsomal oxidases. Similarly, high
copper had no effect on the oxidases. High vitamin A increased
alkaloid dehydrogenase, aniline hydroxylas,:, and
liver weight although the effects were not significant. In
a separate experiment, rats pretreated with above-normal
levels of selenium for five days were less susceptible to
acute intoxication from tansy alkaloids. However, fewer of
the pretreated animals survived (three weeks) the overall
In second-generation-selenium (SGS) deficient rats,
low blood glutathione peroxidase (GPXase), poor growth, alopecia, and cataracts were observed. In males, low
plasma testosterone and low microsomal protein were concurrent
with low levels of microsomal N-demethylase, hydroxylase,
and reductase. Alkaloid dehydrogenase was not affected
by the deficiency. In SGS-deficient females,
neither microsomal protein nor mixed-function oxidase activity
was affected. However, phenobarbital treatment (induction)
resulted in a greater increase in liver weight and a
lesser increase in microsomal protein and alkaloid dehydrogenase
in deficient animals. Pentobarbital sleeping time
was not different in SGS-deficient males and females.
In male rats fed a selenium-deficient diet for 11
months, body weight and blood GPXase were significantly
lower. Mild alopecia, immotile sperm, and lower plasma
testosterone were observed in some animals. N-demethylase
(significantly) and hydroxylase (nonsignificantly) were
less active. Phenobarbital treatment of deficient animals
resulted in a greater increase in liver size and a substantially
lesser increase in alkaloid dehydrogenase and
cytochrome P-450 activity.
Mixed-function oxidase activity was studied in
selenium-deficient chickens and white-muscle diseased lambs.
In chickens, the torula yeast diet produced poor growth and
diarrhea. The selenium deficiency was without effect on
the microsomal oxidases. All the oxidases were consistently
less active in chickens fed a standard diet. In lambs receiving comparable levels of selenium and demonstrating
similar GPXase activity, some were stricken with whitemuscle
disease. Microsomal oxidases were consistently
lower in the diseased individuals.