PHYSICOCHEMICAL AND METABOLIC BASIS FOR THE DIFFERING NEUROTOXICITY OF THE PYRROLIZIDINE ALKALOIDS, TRICHODESMINE AND MONOCROTALINE

Monocrotaline and trichodesmine are structurally closely related pyrro lizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD(50) 57 mu mol/kg) and monocrotalin e pneumotoxic (LD(50) 335 mu mol/kg). We have compared certain physico chemical properties and metabolic activities of these two PAs in order to understand the quantitative and qualitative differences in toxicit y. Both PAs were metabolized in the isolated, perfused rat liver to hi ghly reactive pyrrolic dehydroalkaloids that appear to be responsible for the toxicity of PAs. More dehydrotrichodesmine (468 nmol/g liver) than dehydromonocrotaline (116 nmol/g liver) was released from liver i nto perfusate on perfusion for 1 hr with 0.5 mM of the parent PA. Dehy drotrichodesmine had a significantly longer aqueous half-life (5.4 sec ) than that of dehydromonocrotaline (3.4 sec). In vivo, significantly higher levels of bound pyrroles were found in the brain 18 hr after in jection of trichodesmine (25 mg/kg; i.p.) than were seen following eit her an equal dose (25 mg/kg; i.p.) or an equitoxic dose (90 mg/kg; i.p .) of monocrotaline. Trichodesmine had a higher partition coefficient than monocrotaline for both chloroform and heptane, indicating its gre ater lipophilicity. The pK(a) of trichodesmine (7.07) was only slightl y higher than that of monocrotaline (pK(a) 6.83), suggesting that a di fference in degree of ionization was not a major factor affecting the relative ability of the dehydroalkaloids to cross the blood-brain barr ier. We conclude that the greater lethality and neurotoxicity of trich odesmine compared to monocrotaline is due to two structural characteri stics: (i) steric hindrance at position 14 of dehydrotrichodesmine res ults in greater resistance to hydrolysis, allowing more to be released from the liver and to be delivered to the brain; (ii) the larger isop ropyl substituent at position 14 of dehydrotrichodesmine renders the m olecule more lipophilic, leading to greater penetration of the brain.