Toxicity and in vitro metabolism of Senecio jacobaea pyrrolizidine alkaloids in the rat and mouse

Graduation date: 1986Senecio jacobaea (tansy ragwort) is a common weed in the\ud Pacific Northwest that contains toxic pyrrolizidine alkaloids\ud (PAs). Jacobine, the major PA in Senecio jacobaea, was incubated\ud with rat liver microsomes and metabolites were isolated by high\ud performance liquid chromatography (HPLC) and identified by mass\ud spectrometric analysis. Metabolites included a pyrrolic compound,\ud (R,S) -6,7- dihydro -7- hydroxy- 1- hydroxymethy1 -5H- pyrrolizine (DHP),\ud jacobine N-oxide and jacoline. HPLC analysis using a\ud styrene-divinylbenzene resin reversed-phase column was used to\ud quantify DHP in microsomal incubation extracts. This technique was\ud used to test the effects of induction of microsomal enzymes on the\ud in vitro metabolism of jacobine. The highest specific activity of\ud DHP formation was observed with microsomes from rats treated with\ud phenobarbital.\ud The microsomal metabolism of three other Senecio jacobaea PAs,\ud jacoline, seneciphylline and senecionine, was also studied using\ud HPLC analysis. DHP was observed in each case and the identity of\ud the products from senecionine and seneciphylline was confirmed by\ud mass spectrometry. The N-oxides of these two PAs were also\ud identified by HPLC and mass spectrometry. A microsomal enzyme\ud induction experiment showed that, as with jacobine, phenobarbital\ud treatment increased the specific activity of DHP formation. The\ud specific activity of N-oxide formation was highest with microsomes\ud from untreated rats. The involvement of the microsomal\ud flavoprotein monooxygenase in PA N-oxide formation was tested in\ud thermal inactivation and chemical inhibition experiments. The\ud results showed that the flavoprotein monooxygenase did not play a\ud major role in microsomal N-oxide formation from seneciphylline.\ud The acute toxicities of two of these PAs, jacobine and\ud jacoline, were determined in mice. The effects of drugs affecting\ud hepatic microsomal enzyme levels on the acute toxicity of jacobine\ud was also tested. Jacobine was identified in the urine of rats\ud given an oral dose of the alkaloid