Hepatoprotective effects of cystathionine against acetaminophen-induced necrosis.
The hepatoprotective effects of cystathionine, as a prodrug of cysteine release, were examined in rodents. When cystathionine (100 mg/kg) was administered i.p. in rats, it was eliminated from rat serum with a biological half-life of 1.19 +/- 0.23 hr. Subsequent to the decrease of serum cystathionine, the concentration of cyst(e)ine increased up to 14.5 +/- 1.2 mg/l, and then decreased with a half-life of 4.12 +/- 0.82 hr. The concomitant administration of taurine (100 mg/kg) did not change the half-life of cystathionine (1.42 +/- 0.33 hr), but significantly increased the half-life of cyst(e)ine (19.1 +/- 0.56 hr). This effect of taurine was also observed when cysteine (100 mg/kg) was administered to rats. The liver injury was induced by the i.p. injection of acetaminophen (5.0 mmol/kg). The mortality rates, serum alanine and aspartate aminotransferase activities and the histological analysis of the livers, which were obtained from living mice, were examined 22 hr after the injections. Two administrations of cystathionine (5.0 mmol/kg x 2), one at 20 min before and one 20 min after the acetaminophen injection, prevented the acetaminophen-induced hepatic necrosis, completely. The coadministration of taurine increased the hepatoprotective activity of cystathionine, even at the low dosages (0.18 and 0.55 mmol/kg x 2). Moreover, the treatments using cystathionine, with and without taurine, restored the hepatic glutathione levels to 2.27 +/- 0.23 and 1.80 +/- 0.27 mumol/g, respectively. These levels had been depleted by acetaminophen injection to 0.96 +/- 0.18 mumol/g, 2 hr after the injection. Propargylglycine, an inhibitor of cystathionase, abolished the hepatoprotective effects of cystathionine, although it could not affect the action of cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Clinical Pharmacology, Tottori University School of Medicine, Yonago, Japan.
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Y
Kitamura
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Y
Kamisaki
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T
Itoh
D000082:Acetaminophen / Q000633:toxicity*; D000480:Alkynes; D000818:Animals; D003540:Cystathionine / Q000493:pharmacokinetics / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008099:Liver / Q000032:analysis / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009336:Necrosis; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013654:Taurine / Q000494:pharmacology
D000480:Alkynes; D013654:Taurine; D000082:Acetaminophen; D003540:Cystathionine; C009055:propargylglycine; D010293:Pargyline; D005978:Glutathione; D005998:Glycine