The Metabolic Formation of γ-(3-Pyridyl)-γ-hydroxybutyric Acid and Its Possible Intermediary Role in the Mammalian Metabolism of Nicotine

McKennis, Herbert; Schwartz, Sorell L.; Turnbull, Lennox B.; Tamaki, Einosuke; Bowman, Edward R.

doi:10.1016/s0021-9258(18)91231-7

Cited by 37 publications

(19 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These were synthesized by adaptation of a previously described procedure . Briefly, [pyridine-D 4 ]ethyl nicotinate or [ 13 C 6 ]ethyl nicotinate (0.75 mmol) was added to a suspension of NaH (3.7 mmol, 60% dispersion in mineral oil) in 5 mL of refluxing benzene.…”

Section: Methodsmentioning

confidence: 99%

“…These were synthesized by adaptation of a previously described procedure. 39 Briefly, [pyridine-D 4 ]ethyl nicotinate or [ 13 C 6 ]ethyl nicotinate (0.75 mmol) was added to a suspension of NaH (3.7 mmol, 60% dispersion in mineral oil) in 5 mL of refluxing benzene. After the addition of ethanol (0.5 mL), diethyl succinate (3.75 mmol) was added into the stirred refluxing mixture dropwise, and the reaction was allowed to take place for 45 min.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

See 1 more Smart Citation

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D₄]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

Meng

Wang

Upadhyaya

et al. 2014

Chem. Res. Toxicol.

View full text Add to dashboard Cite

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 1) is a potent tobacco-specific lung carcinogen believed to play a key role in the development of lung cancer in smokers. Metabolic activation of NNK to DNA damaging reactive intermediates proceeds via α-hydroxylation pathways. The end products of these pathways are excreted in the urine of smokers as 4-oxo-4-(3-pyridyl)butanoic acid (keto acid, 3) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid, 4). The sum of these biomarkers (after NaBH4 treatment), referred to as total hydroxy acid, could potentially be used to measure the extent of NNK metabolic activation in smokers. However, the same metabolites are formed from nicotine; therefore, there is a need to distinguish the NNK- and nicotine-derived keto and hydroxy acid in smokers’ urine. We previously developed a unique methodology based on the use of [pyridine-D4]NNK ([D4]1), which metabolizes to the correspondingly labeled biomarkers. In this study, we developed a sensitive and reproducible assay for the detection and quantitation of total [pyridine-D4]hydroxy acid ([D4]4) in human urine. A two-step derivatization approach was used to convert [D4]4 to [pyridine-D4]methyl 4-hexanoyl-4-(3-pyridyl)butanoate ([D4]6), and an LC-ESI-MS/MS method was developed for the analysis of this derivative with excellent sensitivity, accuracy, and precision. The robustness and reproducibility of the assay was further confirmed by its application for the analysis of urine samples from 87 smokers who smoked [D4]1-containing cigarettes for 1 week. The measured level averaged 130 fmol/mL urine. The developed assay can be used in future studies that may require evaluation of the relative efficiency of NNK metabolic activation in humans.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D₄]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

Meng

Wang

Upadhyaya

et al. 2014

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…However, keto acid and hydroxy acid are also formed in nicotine metabolism (Scheme ). They are produced by further metabolism of cotinine, via norcotinine and 5‘-hydroxycotinine ( − ). Nicotine levels in cigarette smoke are 1400−13000 times greater than the combined level of NNK and NNN ( , ).…”

Section: Introductionmentioning

confidence: 99%

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

Trushin

Hecht

1999

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are believed to play a role in cancers associated with the use of tobacco products. Urinary metabolites of NNK and NNN could be used as biomarkers for an individual's ability to metabolically activate or detoxify these nitrosamines. While several metabolites of NNK can be quantified in human urine, no assay is available to determine human urinary levels of NNK and NNN metabolites resulting from the critical alpha-hydroxylation metabolic activation pathways. The major urinary metabolites resulting from alpha-hydroxylation of NNK and NNN in rodents are 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid). The major obstacle to the use of these metabolites as biomarkers of metabolic activation is the fact that they are also metabolites of nicotine, which is present at levels 1400-13000 times greater than those of the nitrosamines in cigarette smoke. However, the chirality of hydroxy acid could be useful in overcoming this problem. If different enantiomers of hydroxy acid were formed from nicotine versus the nitrosamines, and if the overall yield of hydroxy acid from nicotine were substantially smaller than that from the nitrosamines, then hydroxy acid might be useful as a urinary biomarker of NNK and NNN alpha-hydroxylation. To these ends, F-344 rats were administered either [5-3H]NNK, [5-3H]NNN, [5-3H]keto acid, or [2'-14C]nicotine. The levels of urinary hydroxy acid were determined by HPLC analysis. Its stereochemistry was determined by conversion to its methyl ester, reaction with (S)-(-)-alpha-methylbenzyl isocyanate, and separation and quantitation of the resulting diastereomers by HPLC. Urinary hydroxy acid accounted for 12% of the NNK dose and 31% of the NNN dose, but only 1 and 0.1% of the dose of keto acid and nicotine, respectively. Furthermore, metabolism of NNK produced mainly (S)-hydroxy acid in the urine, while metabolism of keto acid and nicotine gave predominantly (R)-hydroxy acid. Both enantiomers were present in the urine of NNN-treated rats. Therefore, in the rat, it is possible to distinguish the hydroxy acid derived from nicotine from that derived from the nitrosamines. If similar pathways occur in humans, (S)-hydroxy acid could potentially be developed as a urinary biomarker of NNK and NNN alpha-hydroxylation in smokers.

show abstract

“…This route was convenient and low cost for industrial production. Similar to the above reaction, Mckennis and co‐workers proposed that 8 was reduced by means of NaBH 4 to obtain 4‐hydroxy‐4‐(pyridin‐3‐yl)butanoic acid, and then was converted to 5‐(pyridin‐3‐yl)dihydrofuran‐2(3H)‐one in a mixture of methanol and concentrated sulfuric acid [67] …”

Section: Synthetic Strategy Of Nicotinementioning

confidence: 89%

“…Similar to the above reaction, Mckennis and co-workers proposed that 8 was reduced by means of NaBH 4 to obtain 4-hydroxy-4-(pyridin-3-yl)butanoic acid, and then was converted to 5-(pyridin-3-yl)dihydrofuran-2(3H)-one in a mixture of methanol and concentrated sulfuric acid. [67] Divi and co-workers reported the 2-pyrrolidone (10) was reacted with butanal to give N-(1-butenyl)-2-pyrrolidone (11), which was condensed with methyl nicotinate (12) to give the important intermediate 13. [61] And then 13 was reacted with hydrochloric acid to obtain myosmine (14).…”

Section: Total Synthesis Of Rac-nicotinementioning

confidence: 99%

Research Progress in the Pharmacological Effects and Synthesis of Nicotine

Zhang

Song

et al. 2022

ChemistrySelect

View full text Add to dashboard Cite

Nicotine is an alkaloid found in solanaceae plants and an important component in tobacco. It is the main substance that causes smoking addiction and can have many effects on the nervous system. In recent years, nicotine has been found to have the value of drug transformation research, which has attracted the attention of a large number of scholars in the fields of organic synthesis and medicinal chemistry. Related drug transformation research and chemical synthesis continue to emerge. This article mainly summarizes the research progress of nicotine pharmacological effects and synthesis.

show abstract

The Metabolic Formation of γ-(3-Pyridyl)-γ-hydroxybutyric Acid and Its Possible Intermediary Role in the Mammalian Metabolism of Nicotine

Cited by 37 publications

References 13 publications

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D₄]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D₄]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

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

Research Progress in the Pharmacological Effects and Synthesis of Nicotine

Contact Info

Product

Resources

About

The Metabolic Formation of γ-(3-Pyridyl)-γ-hydroxybutyric Acid and Its Possible Intermediary Role in the Mammalian Metabolism of Nicotine

Cited by 37 publications

References 13 publications

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D4]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D4]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

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

Research Progress in the Pharmacological Effects and Synthesis of Nicotine

Contact Info

Product

Resources

About

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D₄]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D₄]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers