Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation.
We quantified urinary levels of two metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide, 4-[(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the study. Thirteen used the nicotine patch starting at the quit date, whereas the others used no patch. Two 24-h urine samples were collected on 2 consecutive days before smoking cessation; blood was also obtained. Beginning at their quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The urine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide, and cotinine plus cotinine-N-glucuronide. Some blood samples were also analyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking cessation was much slower than expected. This was clearly demonstrated by comparison with cotinine and nicotine levels in urine. One week after smoking cessation, 34.5% of baseline NNAL plus NNAL-Gluc was detected in urine, whereas the corresponding values for cotinine and nicotine were 1.1 and 0.5%, respectively. Even 6 weeks after cessation, 7.6% of the original levels of NNAL plus NNAL-Gluc remained. In some subjects, NNAL plus NNAL-Gluc were detected 281 days after cessation. The distribution half-life for NNAL and NNAL-Gluc was 3-4 days, whereas the elimination half-life was 40-45 days. Total body clearance of NNAL was estimated to be 61.4 +/- 35.4 ml/min, and volume of distribution in the beta-phase was estimated to be 3800 +/- 2100 liters, indicating substantial distribution into the tissues. Parallel studies in rats treated chronically or acutely with NNK in the drinking water support the conclusion that NNAL has a large volume of distribution. There was no effect of the nicotine patch on levels of NNAL plus NNAL-Gluc, indicating that NNK is not formed endogenously from nicotine. The results of this study demonstrate that NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating the presence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered and slowly released.
Hecht
S S
SS
University of Minnesota Cancer Center, Minneapolis 55455, USA.
Carmella
S G
SG
Chen
M
M
Dor Koch
J F
JF
Miller
A T
AT
Murphy
S E
SE
Jensen
J A
JA
Zimmerman
C L
CL
Hatsukami
D K
DK
D000328:Adult; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics*; D003367:Cotinine / Q000652:urine; D005260:Female; D005965:Glucuronates / Q000493:pharmacokinetics / Q000652:urine*; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000652:urine; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000652:urine; D009602:Nitrosamines / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344; D016540:Smoking Cessation