Inhibition of cytochrome P4502E1 expression by organosulfur compounds allylsulfide, allylmercaptan and allylmethylsulfide in rats.
Cytochrome P4502E1 (CYP2E1) is active in both detoxication and activation of small organic molecules. The effects of organosulfur compounds including allylsulfide (AS), allylmercaptan (AM) and allylmethylsulfide (AMS) on the expression of CYP2E1 were examined in rats. 4-Nitrophenol, aniline hydroxylase and N-nitrosodimethylamine demethylase activities, the rates of which represent the level of CYP2E1, decreased in hepatic microsomes isolated from rats treated with AS in a time-dependent manner by 45% to 90%, as compared to control. Pyrazine-induced hepatic microsomes exhibited approximately 5-fold increases in CYP2E1-catalysed metabolic activities, whereas the hepatic microsomes obtained after treatment of animals with both AS and pyrazine showed rates comparable to or less than those in control microsomes. AM or AMS suppressed constitutive and pyrazine-inducible levels of CYP2E1 similarly to AS. Immunoblot analyses of hepatic microsomes, using an anti-CYP2E1 antibody, showed that AS, AM and AMS significantly suppressed constitutive levels of CYP2E1 apoprotein after 24, 48 and 72 hr. Time-dependent induction of CYP2E1 by pyrazine was also completely blocked by treatment of animals with AS throughout the experimental period, as evidenced by immunoblot analysis. The levels of CYP2E1 apoprotein in the hepatic microsomes isolated from animals treated with both AM and pyrazine, or with both AMS and pyrazine were comparable to those in control hepatic microsomes at days 1-3 post-treatment. Treatment of rats with each of these organosulfur compounds caused no significant changes in the levels of CYP2E1 mRNA, as assessed by slot and northern blot analyses, suggesting that post-transcriptional regulation may be associated with the suppression of CYP2E1 apoprotein levels. The results of metabolic activities, immunoblot analyses and RNA blot analyses demonstrated that these organosulfur compounds are effective in suppressing constitutive and inducible expression of CYP2E1.
Kwak
M K
MK
College of Pharmacy, Seoul National University, Korea.
Kim
S G
SG
Kwak
J Y
JY
Novak
R F
RF
Kim
N D
ND
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000235:genetics; D015536:Down-Regulation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000235:genetics; D011719:Pyrazines; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D013440:Sulfides; C038491:allyl sulfide; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C077207:allyl methyl sulfide