Physicochemical and metabolic basis for the differing neurotoxicity of the pyrrolizidine alkaloids,trichodesmine and monocrotaline |
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Authors: | R J Huxtable C C Yan S Wild S Maxwell R Cooper |
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Institution: | (1) Department of Pharmacology, University of Arizona College of Medicine, 85724 Tucson, Arizona |
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Abstract: | Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic
toxicities, trichodesmine being neurotoxic (LD50 57 μmol/kg) and monocrotaline pneumotoxic (LD50 335 μmol/kg). We have compared certain physicochemical properties and metabolic activities of these two PAs in order to understand
the quantitative and qualitative differences in toxicity. Both PAs were metabolized in the isolated, perfused rat liver to
highly 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 into perfusate on perfusion for 1
hr with 0.5 mM of the parent PA. Dehydrotrichodesmine 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
injection of trichodesmine (25 mg/kg; i.p) than were seen following either 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 greater lipophilicity. The pKa of trichodesmine (7.07) was only slightly higher than that of monocrotaline (pKa 6.83), suggesting that a difference in degree of ionization was not a major factor affecting the relative ability of the
dehydroalkaloids to cross the blood-brain barrier. We conclude that the greater lethality and neurotoxicity of trichodesmine
compared to monocrotaline is due to two structural characteristics: (i) steric hindrance at position 14 of dehydrotrichodesmine
results in greater resistance to hydrolysis, allowing more to be released from the liver and to be delivered to the brain;
(ii) the larger isopropyl substituent at position 14 of dehydrotrichodesmine renders the molecule more lipophilic, leading
to greater penetration of the brain.
Special issue dedicated to Dr. Kinya Kuriyama |
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Keywords: | Pyrrolizidine alkaloids monocrotaline trichodesmine neurotoxicity |
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