Graduate Thesis Or Dissertation
 

Selenium effects and species differences in hepatic metabolism of pyrrolizidine alkaloids and other xenobiotics

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  • 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 bases. 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 effect. 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.
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