Stimulation of microsomal dimethylnitrosamine-N-demethylase by pretreatment of mice with acetone.
To further investigate the relationship between in vivo microsomal enzyme modifiers and in vitro dimethylnitrosamine (DMN) metabolism, male C57BL/6J mice were pretreated with acetone or Aroclor 1254, two compounds known to influence DMN-N-demethylase activity. Pretreatment with acetone enhanced the in vitro microsomal activity of DMN-N-demethylase, as measured by formaldehyde production from DMN. Accompanying this acetone-enhanced demethylase activity was an increase in the covalent binding of [14C]DMN to RNA, protein and DNA. Four distinct Km values dependent on the substrate concentration were observed for the N-demethylase present in control microsomes. Only one Km value was observed for the demethylase in microsomes from acetone-treated animals, but it was significantly lower than the lowest Km observed in the control microsomes. At DMN concentrations of 1 and 10 mM, acetone significantly increased N-demethylation of DMN as compared to control, but not at 100 mM DMN. Aroclor 1254 pretreatment repressed DMN-N-demethylase at 1 mM DMN but enhanced it at 100 mM. These results suggest that there may be multiple forms of DMN-N-demethylase which are dependent on DMN concentration and respond differently to modifiers of the microsomal drug-metabolizing enzymes.
D000096:Acetone / Q000494:pharmacology*; D000818:Animals; D004128:Dimethylnitrosamine / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology*; D009602:Nitrosamines / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D013268:Stimulation, Chemical; D013997:Time Factors
D009602:Nitrosamines; D000096:Acetone; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine