Previous studies using guinea pigs and cats have shown that liver lipid composition is affected by intrahepatic taurine levels. The purpose of the present study was to determine whether this sulfonated amino acid could also affect lipid metabolism in the rat, an animal capable of synthesizing substantial amounts of taurine and used extensively in studies on lipid metabolism. Wide variations in the hepatic taurine content were induced by administering either 1% taurine or 1% guanidinoethane sulfonate in the drinking water for 2 weeks. These treatments increased and decreased taurine liver content, respectively, but did not affect either food or water intakes, or growth rates. The plasma concentrations of the major lipid classes in treated animals did not show any significant alteration in comparison to control animals, except for nonesterified fatty acid levels that were significantly lowered by guanidinoethane sulfonate administration. Taurine supplementation did cause a significant decrease in total hepatic lipid content that was attributable to the reduction of free and esterified cholesterol, triglyceride, and phosphatidylethanolamine hepatic concentrations. This same treatment slightly increased both bile flow and secretion of taurine-conjugated primary bile salts. In particular, the proportion of tauro-beta-muricholate significantly increased, whereas that of taurodeoxycholate greatly decreased. The administration of guanidinoethane sulfonate reduced both the bile flow and the secretion of taurine-conjugated bile salts and caused a significant alteration in the ratio between glycine- and taurine-conjugated bile salts. This did not occur after the treatment with taurine. Interestingly, we observed an inverse correlation between hepatic taurine levels and the proportion of either cholesteryl ester in hepatic lipids or taurochenodeoxycholate in biliary bile salts. These facts suggest that taurine hepatic levels influence mostly hepatic steroid metabolism, but they also affect the metabolism of other lipid classes.
Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD(50) 57 mu mol/kg) and monocrotaline pneumotoxic (LD(50) 335 mu mol/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 pK(a) of trichodesmine (7.07) was only slightly higher than that of monocrotaline (pK(a¿ 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.