Effects of phenethylisothiocyanate on the expression of glutathione S-transferases and hepatotoxicity induced by acetaminophen.
1. The effect of PEITC on the expression of hepatic glutathione S-transferases (GST) and the glutathione (GSH) conjugation has been investigated in the Sprague-Dawley rat, and it has been determined whether hepatotoxicity of acetaminophen (AA) could be inhibited through the induction of GST expression in mouse. 2. The hepatic GST activity and protein levels of alpha class (Ya, Yc) and mu class (Yb1, Yb2) of GST were elevated in a dose-dependent manner after treatment with PEITC (0, 3.16, 10, 31.6, 100 and 200 mg/kg, p.o., 3 days). The mRNA levels of GST Ya and GST Yb1 were also markedly increased 1 day after treatment with PEITC at dosages ranging from 31.6 to 200 mg/kg. The hepatic GSH content was significantly increased to 200% of control at dose of 200 mg/kg PEITC. 3. Pretreatment with 100 mg/kg PEITC significantly enhanced the biliary excretion of glutathione conjugate of AA 2-fold, whereas treatment with 200 mg/kg did not affect it. 4. In mouse, PEITC (100 and 200 mg/kg, 3 days) decreased the lethality and hepatotoxicity caused by AA. 5. These results indicate that (1) the induction of GST by PEITC is presumably under transcriptional regulation, and (2) PEITC may have a protective function against AA-induced hepatotoxicity by induction effect on GST, in combination of enhancement of hepatic GSH.
Seo
K W
KW
Department of Toxicology, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul. kwseo@kfda.go.kr
Kim
J G
JG
Park
M
M
Kim
T W
TW
Kim
H J
HJ
D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000096:biosynthesis*; D017879:Isothiocyanates / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011061:Poly A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D017879:Isothiocyanates; D012333:RNA, Messenger; D011061:Poly A; D000082:Acetaminophen; C058305:phenethyl isothiocyanate; D005982:Glutathione Transferase