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Effect of Pyrrolizidine Alkaloids on Liver Microsome Mixed-Function Oxidase Activity in Rats¹

Oregon State University, Corvallis 97331

⁵ To whom reprint requests should be addressed.

Abstract

The effect of a single ( LD₅₀) dose (65 mg/kg body weight) of pyrrolizidine alkaloid isolated from Senecio jacobaea on liver microsome mixed function oxidase activity in rats was studied. Within 1 hr of dosing, there was a decline (P<.05) in the pyrrole production rate in vitro from pyrrolizidine alkaloid. At 24 hr, there was reduced (P<.01) activity of amino-pyrine N-demethylase, and cytochrome P-450 levels. Spleen weight as a percent of body weight was elevated (P<.01) at 6 days following injection; microsomal protein was lowered (P<.01) at 24 hours. The results suggest that pyrroles produced as a result of hepatic metabolism of pyrrolizidine alkaloids directly inhibit (by 1 hr) the enzymes involved in their own production. They inhibit aminopyrine N-demethylase and cytochrome P-450 activity, probably via effects on protein synthesis or protein degradation.

¹ Oregon Agricultural Experiment Station Technical Paper No. 4202.

² Department of Animal Science.

³ Present address: Department of Dairy Science, Michigan State University, East Lansing.

⁴ Present address: College of Veterinary Medicine, Colorado State University, Fort Collins.