| Autor: |
Kozlovich S; Department of Pharmaceutical Sciences, College of Pharmacy , Washington State University , Spokane Washington 99210 , United States., Chen G; Department of Pharmaceutical Sciences, College of Pharmacy , Washington State University , Spokane Washington 99210 , United States., Watson CJW; Department of Pharmaceutical Sciences, College of Pharmacy , Washington State University , Spokane Washington 99210 , United States., Lazarus P; Department of Pharmaceutical Sciences, College of Pharmacy , Washington State University , Spokane Washington 99210 , United States. |
| Jazyk: |
angličtina |
| Zdroj: |
Chemical research in toxicology [Chem Res Toxicol] 2019 Aug 19; Vol. 32 (8), pp. 1689-1698. Date of Electronic Publication: 2019 Jul 30. |
| DOI: |
10.1021/acs.chemrestox.9b00217 |
| Abstrakt: |
Tobacco specific nitrosamines (TSNAs) are among the most potent carcinogens found in cigarettes and smokeless tobacco products. Decreases in TSNA detoxification, particularly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have been associated with tobacco-related cancer incidence. NNK is metabolized by carbonyl reduction to its major carcinogenic metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is detoxified by glucuronidation at the nitrogen within the pyridine ring or at the chiral alcohol to form four glucuronide products: ( R )-NNAL- O -Gluc, ( S )-NNAL- O -Gluc, ( R )-NNAL- N -Gluc, ( S )-NNAL- N -Gluc. Stereoselective NNAL-Gluc formation and the relative expression of NNAL-glucuronidating UGTs (1A4, 1A9, 1A10, 2B7, 2B10, 2B17) were analyzed in 39 tissue specimens from the upper aerodigestive tract (esophagus ( n = 13), floor of mouth ( n = 4), larynx ( n = 9), tongue ( n = 7), and tonsil ( n = 6)). All pooled tissue types preferentially formed ( R )-NNAL- O -Gluc in the presence of racemic-NNAL; only esophagus exhibited any detectable formation of ( S )-NNAL- O -Gluc. For every tissue type examined, UGT1A10 exhibited the highest relative expression levels among the NNAL- O -glucuronidating UGTs, ranging from 36% (tonsil) to 49% (esophagus), followed by UGT1A9 > UGT2B7 > UGT2B17. UGT1A10 also exhibited similar or higher levels of expression as compared to both NNAL- N -glucuronidating UGTs, 1A4 and 2B10. In a screening of cells expressing individual UGT enzymes, all NNAL glucuronidating UGTs exhibited some level of stereospecific preference for individual NNAL enantiomers, with UGTs 1A10 and 2B17 forming primarily ( R )-NNAL- O -Gluc. These data suggest that UGTs 1A10 and 2B17 may be important enzymes in the detoxification of TSNAs like NNK in tissues of the upper aerodigestive tract. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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