Modulation of reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by vitamin C-palmitate.
An in vitro study of effects of vitamin C-palmitate on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rat microsomes was performed. A sensitive assay method has been developed for the detection of metabolites of NNK in microsomes. Only the reduced metabolite of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL), was detected and measured in a time-course study. Vitamin C-palmitate enhanced the reduction of NNK in a concentration-dependent manner. The results indicate a significant increase in Vmax and K(m) in the presence of vitamin C. However, the rate of formation of NNAL at low substrate concentration varied. The ratio of Vmax to K(m) decreases. The results suggest that the kinetics are accounted for best by an uncompetitive activator binding model at low concentration of vitamin C. The uncompetitive binding model becomes sketchy at higher concentration of vitamin C. These observations infer that vitamin C loosely binds to the substrate-enzyme complex. Furthermore, the nature of the binding would facilitate the modulation of NNK biotransformation leading to the formation of NNAL. The results also show that vitamin C-palmitate is a potent activator of NNK reduction in rat liver microsomes. Thus, vitamin C-palmitate would mediate the metabolism of NNK through reduction. The resulting NNAL-glucuronide is more readily eliminated in urine.
Leung
Y K
YK
Department of Biochemistry, Chinese University of Hong Kong, Shatin, Hong Kong.
Ho
J W
JW
D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002273:Carcinogens / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D004798:Enzymes / Q000187:drug effects / Q000378:metabolism; D008658:Inactivation, Metabolic; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism*; D009602:Nitrosamines / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D004798:Enzymes; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D019392:Cytochrome P-450 CYP2E1; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid