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Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation
S S Hecht1, S G Carmella, M Chen
1University of Minnesota Cancer Center, Minneapolis 55455, USA.
Abstract:
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.
Insights
Urinary levels of tobacco carcinogen metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide (NNAL-Gluc) decline slowly after smoking cessation. These compounds are retained in the body for extended periods, unlike nicotine and cotinine.
Area of Science:
- Toxicology
- Pharmacokinetics
- Cancer Research
Background:
- Tobacco-specific nitrosamines, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are potent lung carcinogens.
- Metabolites of NNK, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide (NNAL-Gluc), are biomarkers of exposure and potential contributors to carcinogenicity.
Purpose of the Study:
- To quantify the urinary excretion kinetics of NNAL and NNAL-Gluc in individuals who have ceased smoking.
- To compare the elimination rates of NNAL/NNAL-Gluc with those of nicotine and cotinine after smoking cessation.
- To investigate the potential endogenous formation of NNK from nicotine.
Main Methods:
- Collected 24-hour urine samples from 27 participants before and up to 126 days after smoking cessation.
- Analyzed urine for NNAL, NNAL-Gluc, nicotine, nicotine-N-glucuronide, cotinine, and cotinine-N-glucuronide.
- Determined elimination half-lives, body clearance, and volume of distribution for NNAL and NNAL-Gluc.
Main Results:
- Urinary NNAL and NNAL-Gluc declined significantly slower than nicotine and cotinine after smoking cessation.
- One week post-cessation, 34.5% of baseline NNAL/NNAL-Gluc remained, compared to 1.1% for cotinine and 0.5% for nicotine.
- NNAL and NNAL-Gluc were detected in some subjects up to 281 days after cessation, with an elimination half-life of 40-45 days.
- Nicotine patch use did not affect NNAL/NNAL-Gluc levels, suggesting NNK is not formed endogenously from nicotine.
Conclusions:
- NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating sequestration in a tissue compartment.
- These findings highlight the long-term retention of NNK metabolites, potentially contributing to sustained cancer risk.
- The slow elimination necessitates consideration in biomarker studies and risk assessment following smoking cessation.