Evaluation of 4-(N-methylnitrosamino)-4-(3-pyridyl)butyric acid as a potential monitor of endogenous nitrosation of nicotine and its metabolites

Abstract

The potential endogenous nitrosation of nicotine and cotinine to yield 4-(N-methylnitrosamino)-4-(3-pyridyl)butyric acid (Iso-NNAC) has been studied in smokers and non-smokers. Following i.v. administration of 100 micrograms Iso-NNAC to rats, excretion in urine (67.4 +/- 25.4%) and feces (6.1 +/- 1.6%) occurred within 24 h. The urinary excretion of nitrate, nicotine, cotinine and Iso-NNAC were determined in 24 h urine samples from 19 smokers and 10 non-smokers. Iso-NNAC excretion was found on four occasions (44, 65, 74 and 163 ng/day) in smokers; non-smokers did not excrete Iso-NNAC. Oral administration of nicotine (n = 8; 12-40 mg) and cotinine (n = 3; 40-60 mg) to abstinent smokers did not result in Iso-NNAC excretion, even after oral nitrate (150 mg) supplementation. However, Iso-NNAC was found in cigarette tobacco (10-330 ng/g) and mainstream cigarette smoke (1.1-5.5 ng/cig.). Our studies suggest that the occasional presence of Iso-NNAC in smokers' urine results from exogenous exposure to the preformed compound in mainstream cigarette smoke and not from endogenous nitrosation of nicotine and its metabolites.

Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines

“…In this respect, iso-NNAC is similar to other nitrosamino acids. There is no evidence for endogenous formation of iso-NNAC in humans exposed to nicotine or cotinine (431).…”

“…iso-NNAC is inactive in the hepatocyte primary culture DNA repair assay and as a tumorigen in the A/J mouse (286,301,429). Approximately 75% of iso-NNAC is excreted unchanged in the rat, mainly in the urine (430,431). In this respect, iso-NNAC is similar to other nitrosamino acids.…”

An Analysis of the Role of Tobacco-Specific Nitrosamines in the Carcinogenicity of Tobacco Smoke

“…Some scientists have hypothesized that ingested tobacco alkaloids, such as nicotine, might contribute to TSNA formation within the human body (Hoffmann et al 1994; Hecht and Hoffmann 1989). Others have published data that support the conclusion that endogenous TSNA formation does not occur (Fischer et al 1990; Caldwell et al 1991; Meger et al 1995; Adlkofer 1995; Spiegelhalder and Fischer 1990; Hecht et al 1999; Tricker et al 1993). The hypothesis of endogenous TSNA formation conflicts with recent evidence that smoking cessation therapies that involve the administration of nicotine in the form of gum, patch, and/or inhalers do not lead to endogenous TSNA formation (Hecht et al 1999).…”