Comprehensive analysis of urinary metabolites of N′ -nitroso-nornicotine

Hecht, Stephen S.; Lin, Dana T.; Chen, Chi hong B.

doi:10.1093/carcin/2.9.833

Cited by 46 publications

(55 citation statements)

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“…In the patas monkey, 5Ј-hydroxylation of NNN appears to exceed 2Ј-hydroxylation, which is consistent with results obtained in human liver microsomes (Staretz et al, 1997). Rodent 2Ј-hydroxylation appears to be more extensive than that observed here (Hecht et al, 1981).…”

Section: Discussioncontrasting

confidence: 51%

“…Pharmacokinetic considerations also suggest that 3Ј-hydroxynorcotinine is not a metabolite of norcotinine. Moreover, norcotinine is excreted in urine mainly unchanged after administration to rats; the only metabolite detected was the keto acid (Hecht et al, 1981). Rat liver microsomes convert norcotinine to 4-oxo-4-(3-pyridyl)butyramide and nicotinamide (Eldirdiri et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Upadhyaya¹,

Zimmerman

Hecht³

2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:N-Nitrosonornicotine (NNN) is present in significant quantities in tobacco and tobacco smoke and is believed to play an important role as a cause of cancer in people who use tobacco products. Biomarkers of NNN uptake in humans such as urinary metabolites would be useful for assessing cancer risk. Previous studies, carried out almost exclusively in rodents, have characterized urinary metabolites of NNN, but none of these would be suitable as a biomarkers of NNN uptake in humans. Therefore, we studied NNN metabolism in the patas monkey. Monkeys were treated intravenously with

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Upadhyaya¹,

Zimmerman

Hecht³

2002

Drug Metab Dispos

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“…The HPLC apparatus has been described previously (14). Separation of deoxyribonucleosides obtained by DNA hydrolysis was performed with a pu-Bondapak-C15 column (4.9 mm x 30 cm) (Waters Associated, Milford, MA) and with a gradient of 0 to 35% aqueous methanol in 50 min.…”

Section: Chemicalsmentioning

confidence: 99%

“…With NNA1, DNA methylation after 24 hr was associated with the oxidation of a small fraction of NNA1 to NNK. F344 rats were either treated with a single dose of NNK and sacrificed 4 hr later or were administered 14 daily doses of NNK and sacrificed 24 hr later. As shown in Table 3, 06-MedGuo was found only in nasal mucosa, lung and liver.…”

Section: Chemicalsmentioning

confidence: 99%

Study of DNA methylation by tobacco-specific N-nitrosamines.

Castonguay¹,

Foiles²,

Trushin³

et al. 1985

Environ Health Perspect

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An enzyme-linked immunosorbent assay (BA-ELISA) involving use of biotin-labeled anti-rabbit IgG and avidin-labeled horseradish peroxidase was developed for the measurement of 06-methyl-2'-deoxyguanosine (06-MedGuo). Up to 5 jg of methylated DNA was enzymatically hydrolyzed, and the extent of inhibition of binding of immobilized 06-MedGuo-bovine serum albumin to rabbit anti-O6-MedGuo was measured. Fifty percent inhibition of antigen-antibody binding was achieved with 2.5 pmole of of 06-MedGuo. Separation of 0-MedGuo from unmodified nucleosides by high-performance liquid chromatography (HPLC-BA-ELISA) allowed detection of 700 fmole 06-MedGuo in 1 mg of DNA.Among the tobacco-related carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent. In F344 rats it induces nasal cavity, lung and liver tumors. Four hours after a single IV injection of NNK to F344 rats (87 mg/kg body weight), 0'-MedGuo was present in target organs (,umole 0'-MedGuo/mole dGuo) (nasal mucosa, 219; lung, 13.2; and liver, 34.5) but was not detectable in nontarget organs. F344 rats receiving daily IP injections of NNK (40 mg/kg body weight) for 14 days were sacrificed 24 hr after the last injection. The levels of (06-Medguo/dGuo) were 7.9 and 11.4 ,umole/mole in the nasal mucosa and lung, respectively. In the liver no 06-MedGuo was detected, but 1050 ,umole of 7-MeGua/mole Gua was measured by HPLC-fluorimetry. No DNA methylation was observed in the nasal mucosa or liver of F344 rats treated with the nicotine-derived carcinogen N'-nitrosonornicotine. Reduction of the carbonyl of NNK is a major metabolic pathway, giving rise to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol (NNAI). Nasal mucosae were cultured in vitro with NNK or NNAI. After 1 hr, methylation at the 06-dGuo and 7-dGuo sites were observed with NNK but not with NNAI. Methylation by NNAI after 24 hr was associated with the conversion of NNAI to NNK. These results suggest that NNAI is not associated with the activation of NNK to DNA methylating species.

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“…In contrast, myosmine was found in trace quantities as urinary metabolite of NNN in rats. To investigate the further degradation of NNN metabolites, myosmine has been administered s.c. to rats at a dose of 100 mg/kg, and 4-oxo-4-(3-pyridyl)butyric acid (keto acid) was identified as the main metabolite (Hecht et al, 1981).…”

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confidence: 99%

Metabolism of Myosmine in Wistar Rats

Zwickenpflug

Tyroller²,

Richter³

2005

Drug Metab Dispos

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ABSTRACT:The alkaloid myosmine is present not only in tobacco products but also in various foods. Myosmine is easily nitrosated, yielding 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and the esophageal tobacco carcinogen N-nitrosonornicotine. Due to its widespread occurrence, investigations on the metabolism and activation of myosmine are needed for risk assessment. Therefore, the metabolism of myosmine has been studied in Wistar rats treated with single oral doses of [pyridine-5-3 H]myosmine at 0.001, 0.005, 0.5, and 50 mol/kg body weight. Oral administration was achieved by feeding a labeled apple bite. Radioactivity was completely recovered in urine and feces within 48 h. At the two lower doses, 0.001 and 0.005 mol/kg, a higher percentage of the radioactivity was excreted in urine (86.2 ؎ 4.9% and 88.9 ؎ 1.7%) as compared with the higher doses, 0.5 and 50 mol/kg, where only 77.8 ؎ 7.3% and 75.4 ؎ 6.6% of the dose was found in urine. Within 24 h, urinary excretion of radioactivity was nearly complete with less than 4% of the total urinary output appearing between 24 and 48 h. The two major metabolites accounting for >70% of total radioactivity in urine were identified as 3-pyridylacetic acid (20-26%) and 4-oxo-4-(3-pyridyl)butyric acid (keto acid, 50-63%) using UV-diode array detection and gas chromatography-mass spectrometry measurements. 3-Pyridylmethanol (3-5%), 3-hydroxymyosmine (2%) and HPB (1-3%) were detected as minor metabolites. 3-Hydroxymyosmine is exclusively formed from myosmine and therefore might be used as a urinary biomarker for myosmine exposure in the future.

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Comprehensive analysis of urinary metabolites of N′ -nitroso-nornicotine

Cited by 46 publications

References 0 publications

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Study of DNA methylation by tobacco-specific N-nitrosamines.

Metabolism of Myosmine in Wistar Rats

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