Correlation between the Urine Profile of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Metabolites and N7-Methylguanine in Urothelial Carcinoma Patients

Abstract

A major carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is present in cigarette smoke and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), is used as an exposure biomarker for environmental tobacco smoke (ETS). This metabolite (NNAL) can be either detoxified into glucuronidated NNAL (NNAL-Gluc) or activated into an unstable reactive metabolite that methylates DNA along with formation of 4-hydroxy-4-(3-pyridyl)-butyric acid [hydroxy acid (HA)]. Therefore, the carcinogenic risk associated with ETS exposure is greatly modulated by individual variations in metabolic activation and detoxification capabilities. In this study, we defined the urinary HA/total NNAL [HA/total NNAL] ratio as the activation index and NNAL-Gluc/free NNAL [(total NNAL-free NNAL)/free NNAL] ratio as the detoxification index of NNK. The major methylated DNA adduct N 7 -methylguanine (N 7 -MeG), considered as the carcinogenic biomarker for cigarette smoking, was excreted in urine. The objective of this study was to investigate the effects of these metabolic indexes of NNK on N 7 -MeG urinary excretion in a population of urothelial carcinoma patients. Urinary levels of total NNAL (free NNAL plus NNAL-Gluc), free NNAL, HA, and N 7 -MeG were positively correlated with smoking. Furthermore, activation index and detoxification index correlated positively and negatively with N 7 -MeG levels, respectively. Our results suggest that these metabolic indices may represent the phenotype of individual metabolism capability and modulate the carcinogenic risk of ETS exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3390 -5)

Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice

“…NNK is the potent carcinogen in cigarette smoke and TCDD is the most potent AhR agonist among dioxins. Because NNK metabolites and TCDD are detectable in human specimens of the general population [26][27][28][29], it is possible that NNK may interact with TCDD and enhance cancer risks in the general population, such as lung cancer. In our present study, we demonstrated that the combined treatment of NNK and TCDD at non-carcinogenic doses significantly increased the incidence of lung adenoma in A/J mice.…”

Joint Effect of Arsenic Methylation Profile and NNK Metabolites on Urothelial Carcinoma

“…5 Linearity was observed for NNAL and hydroxy acid compounds (r 2 ϭ 0.999), with detection limits ranging from 0.2 to 2.4 pg on column and 0.01 to 0.12 ng/ml in injected samples. Precision and accuracy were determined by analyzing urine collected from a nonsmoker spiked with 1 ng/ml d 3 -NNAL (quality control samples).…”

“…4 Environmental tobacco smoke is thought to be a risk factor for bladder cancer. 5 The nicotine derived, tobacco specific nitrosamine NNK has also been linked to tobacco related human malignancies. 6 NNK is a procarcinogen that requires metabolic activation by cytochrome P450 enzymes to exhibit its carcinogenic effects.…”

“…12 Our previous study showed that the urinary levels of total NNAL, free NNAL and N 7 MeG were positively correlated with cigarette smoking. 5 An epidemiological study demonstrated that the incidence of bladder cancer was significantly associated with chronic arsenic exposure. 13 Inorganic arsenic is biotransformed in humans to MMA V and DMA V .…”

A correlation study applied to biomarkers of internal and effective dose for acrylonitrile and 4-aminobiphenyl in smokers

“…It can be formed by the α-hydroxylation pathway of NNK, but is not specific to NNK since adduct can also be formed by other methylating agents. A moderate correlation was reported between free NNAL and N 7 -MEG in a group of urothelial carcinoma patients split between smokers and non-smokers (Lee et al, 2008). BPDE-haemoglobin adducts but not the albumin adduct were highly correlated with the urinary polyaromatic hydrocarbon 1-hydroxypyrene (Tzekova et al, 2004).…”