Formation of NADP(H) analogs of tobacco-specific nitrosamines in rat liver and pancreatic microsomes.
The metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was examined in rat pancreatic microsomes. No pyridine N-oxidation or alpha-hydroxylation were observed in these preparations. However, one unidentified metabolite of NNAL (unknown A) and two unknown metabolites of NNK (unknowns B and C) were formed. These metabolites were also detected in rat liver microsomal incubations of NNK and NNAL. Studies using [5-3H]-NNK and [Me-3H]NNK demonstrated that the metabolites contained both the pyridyl and methyl portions of the parent compound. Similar results were obtained with NNAL. Formation of unknown C required active microsomes, NADP+, and an NADPH regenerating system. The regenerating system was not required for the formation of NNAL unknown metabolite A or NNK unknown metabolite B. Chemical characterization of unknowns A and B by NMR, UV, and electrospray ionization MS demonstrated that they are NADP+ analogs in which the nicotinamide portion has been replaced by NNAL or NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol adenosine dinucleotide phosphate [(NNAL)ADP+] and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone adenosine dinucleotide phosphate [(NNK)ADP+]. Unknown C was identified as (NNK)ADPH. Both (NNK)ADP+ and (NNK)ADPH were formed from NNK while only (NNAL)ADP+ was produced from NNAL. These NADP+ derivatives were also formed when porcine brain NAD+ glycohydrolase was incubated with NADP+ and NNK or NNAL. These results indicate that NNK and NNAL are substrates for rat liver and pancreatic microsomal NAD+ glycohydrolase-catalyzed transglycosylation reactions.
Peterson
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LA
American Health Foundation, Valhalla, New York 10595.
Ng
D K
DK
Stearns
R A
RA
Hecht
S S
SS
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006868:Hydrolysis; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000378:metabolism; D009249:NADP / Q000378:metabolism*; D009536:Niacinamide / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*; D010947:Plants, Toxic; D051381:Rats; D011916:Rats, Inbred F344; D013056:Spectrophotometry, Ultraviolet; D014026:Nicotiana / Q000378:metabolism*
D002273:Carcinogens; D009602:Nitrosamines; D009536:Niacinamide; D009249:NADP; D000244:Adenosine Diphosphate; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D009244:NAD+ Nucleosidase