Journal
DRUG METABOLISM AND DISPOSITION
Volume 36, Issue 5, Pages 824-830Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.107.019406
Keywords
-
Categories
Funding
- NCI NIH HHS [R01-CA75074, P01-CA68384, R01 CA075074, P01 CA068384-08, P01 CA068384] Funding Source: Medline
- NIDCR NIH HHS [R01 DE013158-08, R01 DE013158, R01-DE13158] Funding Source: Medline
Ask authors/readers for more resources
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol( NNAL) is an important tobacco-specific nitrosamine (TSNA) in the etiology of tobaccorelated cancers, and N-glucuronidation is an important mechanism of NNAL detoxification. In the present study, an analysis of the UDP-glucuronosyltransferases (UGTs) responsible for the N-glucuronidation of the TSNAs N'-nitrosonornicotine, N'-nitrosoanabasine, and N'-nitrosoanatabine was performed. Using human embryonic kidney 293 cells overexpressing UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, and UGT2B17, only UGT1A4 and UGT2B10 exhibited N-glucuronidating activity against these TSNAs. The KMs for UGT2B10 were 15 to 22-fold lower than those of UGT1A4 against the three TSNAs and were similar to those observed for microsomes prepared from human liver specimens. The overall activity of UGT2B10 was 3.6 to 27-fold higher than UGT1A4 against the three TSNAs as determined by Vmax/ KM after normalization by levels of UGT2B10 versus UGT1A4 mRNA. Similarly high levels of activity were also observed for UGT2B10 against a fourth TSNA, NNAL, exhibiting a 6.3- fold lower KM and 3-fold higher normalized Vmax/ KM than that observed for UGT1A4. Real-time polymerase chain reaction analysis showed that UGT2B10 was expressed at a level that, on average, was 26% higher than that observed for UGT1A4 in a screening of normal liver tissue specimens from 20 individual subjects. These data suggest that UGT2B10 is likely the most active UGT isoform in human liver for the N-glucuronidation of TSNAs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available