Stereoselective Metabolism of Nicotine and Tobacco-Specific <i>N-</i>Nitrosamines to 4-Hydroxy-4-(3-pyridyl)butanoic Acid in Rats

Trushin, Neil; Hecht, Stephen S.

doi:10.1021/tx980213q

Cited by 30 publications

(30 citation statements)

References 25 publications

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“…In this context, only 1.1% of [5-3 H]keto acid i.v. administered to F344 rats was metabolized to hydroxy acid, whereas 94.8% of the keto acid was excreted unmetabolized (Trushin and Hecht, 1999). In case that hydroxy acid is exclusively formed from keto acid, the percentage expected in myosmine metabolism would be approximately 0.5% of all metabolites and therefore below the detection limit in the present study.…”

Section: Metabolism Of Myosmine In Ratscontrasting

confidence: 56%

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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Section: Metabolism Of Myosmine In Ratscontrasting

confidence: 56%

Metabolism of Myosmine in Wistar Rats

Zwickenpflug

Tyroller²,

Richter³

2005

Drug Metab Dispos

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“…Peak 1 was identified as the hydroxy acid by coelution with a standard. The assignment was confirmed by converting the urinary hydroxy acid to its methyl ester then allowing it to react with (S)-(Ϫ)␣-methylbenzyl isocyanate, as described previously (Trushin and Hecht, 1999). The resulting carbamate diastereomers coeluted with standards.…”

Section: Fig 4 Gc-positive Ion Ci-ms Analysis Of Materials Obtained mentioning

confidence: 89%

“…Since nicotine levels in tobacco products are as much as 10,000 times greater than those of NNN, the hydroxy acid and keto acid cannot be used as specific biomarkers of NNN uptake Trushin and Hecht, 1999). Metabolites of NNN that retain unique structural features related to NNN, such as NNN-N-oxide, 3Ј-hydroxyNNN, and 4Ј-hydroxyNNN, are relatively minor urinary metabolites in rodents.…”

Section: Nnnmentioning

confidence: 99%

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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“…HA is the most abundant NNK metabolite detected in urine and it is also produced during N ¶-nitrosonornicotine and nicotine metabolism (33)(34)(35). However, the formation of HA from N ¶-nitrosonornicotine and nicotine is not accompanied with N 7 -MeG generation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the formation of HA from N ¶-nitrosonornicotine and nicotine is not accompanied with N 7 -MeG generation. It has been shown that 12% of urinary HA is generated from NNK, 31% from N ¶-nitrosonornicotine, 1% from keto acid, and only 0.1% from nicotine in rats (33). More recently, Stepanov et al (36) showed that the levels of NNKderived HA were much higher than the levels of total NNAL in smokers.…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Hsueh

Chung

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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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)

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Stereoselective Metabolism of Nicotine and Tobacco-Specific N-Nitrosamines to 4-Hydroxy-4-(3-pyridyl)butanoic Acid in Rats

Cited by 30 publications

References 25 publications

Metabolism of Myosmine in Wistar Rats

Metabolism of Myosmine in Wistar Rats

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

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

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