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 po) 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.