[Inhibitory effect of 2-(N-acetyl-methyl amino)-3',4'-methylenedioxyacetyl-aminophene(SY-640) on covalent binding of carcinogenic benzo(a)pyrene with mouse hepatocyte nuclear DNA].
Many carcinogens must be first transformed into electrophilic ultimate carcinogens via metabolic activation in liver microsomes before covalent binding to nucleophilic center of DNA. SY-640 is a synthetic compound with hepatoprotective activity. Results of the present study indicate that the covalent binding of 3H-benzo(a)pyrine to mouse hepatocyte nuclear DNA in vitro and in vivo was markedly inhibited by SY-640. Further studies found that the liver microsomal cytochrome P-450 content and aminopyrine demethylase activity were significantly increased in mice treated with SY-640 (150 mg.kg-1 p.o.) once daily for three days, while the hepatic microsomal aminopyrine demethylase activity was obviously inhibited two hours after oral administration of SY-640 150 mg.kg-1 in mice. The aminopyrine demethylase activity of liver microsomes from normal, PB- and 3-MC-treated mice was also significantly inhibited by the addition of SY-640 in vitro. When SY-640 was incubated with NADPH-reduced mouse liver microsomes, a metabolic-intermediate(MI) complex at 457 nm was formed. The effects of SY-640 on cytochrome P-450 and its formation of MI complex with cytochrome P-450 may partially explain why SY-640 could inhibit covalent-binding of BP to mouse hepatocyte DNA in vitro.
Li
P F
PF
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050.
Liu
G T
GT
D000081:Acetamides / Q000494:pharmacology*; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*
D000081:Acetamides; D002273:Carcinogens; C097411:SY 640; D001564:Benzo(a)pyrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D000633:Aminopyrine N-Demethylase