EFFECTS OF TAURINE AND GUANIDINOETHANE SULFONATE ON TOXICITY OF THE PYRROLIZIDINE ALKALOID MONOCROTALINE

Monocrotaline (MONO), a pyrrolizidine alkaloid, causes pulmonary arter ial hypertension and right ventricular hypertrophy due to hepatic meta bolism to the alkylating pyrrole dehydromonocrotaline. Taurine, a sulf onic amino acid, is hepato- and cardioprotective in a variety of condi tions. We have examined the effects of taurine and its amidino analog, guanidinoethane sulfonate (GES), in rats injected i.p. with MONO (65 mg/kg). Taurine and GES were given as 1% solutions in drinking water b eginning 14 days before administration of MONO and continuing for 14 d ays thereafter, when the rats were killed. The MONO group had right ve ntricular hypertrophy and pulmonary hyperplasia. Compared with control , no significant changes in the right ventricle/left ventricle weight ratio, or the right ventricle/body weight ratio occurred in rats also given taurine or GES. Lung weights in these two groups were higher tha n in the control group, but below that of the MONO-alone group. The le thality of MONO over 14 days was decreased by taurine (LD(50) for MONO alone 80 mg/kg; for MONO + taurine 121 mg/kg). Rats given only MONO h ad lower hepatic concentrations of GSH and cysteine (Cys), and higher activities of microsomal GSH transferase and gamma-glutamyl transpepti dase. In rats also receiving taurine, hepatic GSH levels and GSH trans ferase activity were no different from control. gamma-Glutamylcysteine (Glu-Cys) synthetase and gamma-glutamyl transpeptidase activities wer e elevated. In MONO-injected rats given GES, hepatic GSH levels were h igher and Cys levels were lower than in either the MONO alone or MONO + taurine groups. gamma-Glu-Cys synthetase activity was depressed. Mic rosomal GSH transferase, GSH peroxidase and gamma-glutamyl transpeptid ase activities were elevated. Livers of MONO-injected animals showed h igher levels of serine (reversed by both taurine and GES) and glycine (Gly; reversed by GES) and lower levels of glutamine. Compared with co ntrol rats, the following changes occurred in serum amino acids: MONO alone: increased aspartate, taurine and lysine; taurine-supplemented: increased taurine, methionine (Met) and lysine, and decreased Gly; GES -supplemented: decreased asparagine, serine, Gly, arginine, taurine, a nd valine. Compared with the MONO-alone group, the taurine-supplemente d group had higher glutamate (Glu), Met and alanine, and the GES-suppl emented group higher alanine and lower serine, Gly, arginine and valin e. We conclude that taurine protects against MONO-induced lethality an d right ventricular hypertrophy. GES also protects against right ventr icular hypertrophy. However, these agents act by different mechanisms, taurine preventing many of the biochemical changes induced by MONO, w ith GES inducing additional changes.