Effects of vitamins and common drugs on reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rat microsomes.
4-(Methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) is a tobacco-specific nitrosamino that requires metabolic activation by cytochrome P450 enzymes. The activation of NNK by cytochrome P450 enzymes leads to the formation of different metabolites. Detoxification of NNK usually occurs via carbonyl reduction to its hydroxyl product, 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL). In the present study, the influences of common vitamins and P450 modulators on the reduction of NNK by rat microsomes were studied. The formation of NNAL but not other metabolites was detected by the described HPLC method. Among the vitamins tested, vitamins E, A (retinol), B6 and B5 were found to be marginal effective upon reduction of NNK while vitamins A (cis-acid), A (trans-acid), D2, D3, K1, K3, B1 and A (crocetin) increased the formation of NNAL from 3 to 21%. The effect of vitamin C-palmitate (<10 microM) was most pronounced followed by crocetin upon reduction of NNK. Clonidine, tolbutamide and atropine slightly increased the reduction of NNK while cimetidine showed no effects. The modulation of NNK reduction could reduce the carcinogenic potential of NNK, since the main detoxification pathway of NNK involves carbonyl reduction.
Leung
Y K
YK
Department of Biochemistry, The Chinese University of Hong Kong, Shatin.
Ho
J W
JW
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D008063:Thioctic Acid / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D014815:Vitamins / Q000737:chemistry / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000975:Antioxidants; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D018727:Muscarinic Antagonists; D009602:Nitrosamines; D014815:Vitamins; D008063:Thioctic Acid; D001285:Atropine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D003000:Clonidine