Glucuronidation of tobacco-specific nitrosamines by UGT2B10

Gang Chen; Ryan W Dellinger; Dongxiao Sun; Thomas E Spratt; Philip Lazarus

doi:10.1124/dmd.107.019406

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Glucuronidation of tobacco-specific nitrosamines by UGT2B10

Journal article

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Peer reviewed

Glucuronidation of tobacco-specific nitrosamines by UGT2B10

Gang Chen, Ryan W Dellinger, Dongxiao Sun, Thomas E Spratt and Philip Lazarus

Drug metabolism and disposition, Vol.36(5), pp.824-830

05/2008

DOI: https://doi.org/10.1124/dmd.107.019406

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https://hdl.handle.net/2376/106936

PMCID: PMC2714266

PMID: 18238858

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Abstract

Cell Line

Glucuronosyltransferase - genetics

Gene Expression

Tobacco

Glucuronides - metabolism

Nitrosamines - metabolism

Humans

Microsomes, Liver - metabolism

RNA, Messenger - metabolism

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is an important tobacco-specific nitrosamine (TSNA) in the etiology of tobacco-related 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 K(M)s 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 V(max)/K(M) 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 K(M) and 3-fold higher normalized V(max)/K(M) 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.

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Title: Glucuronidation of tobacco-specific nitrosamines by UGT2B10
Creators: Gang Chen - Penn State Cancer Institute, Hershey, PA 17033, USA
Ryan W Dellinger
Dongxiao Sun
Thomas E Spratt
Philip Lazarus
Publication Details: Drug metabolism and disposition, Vol.36(5), pp.824-830
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: P01 CA068384-08 / NCI NIH HHS R01 DE013158-08 / NIDCR NIH HHS R01 DE013158 / NIDCR NIH HHS R01-CA75074 / NCI NIH HHS R01 CA075074 / NCI NIH HHS P01 CA068384 / NCI NIH HHS R01-DE13158 / NIDCR NIH HHS P01-CA68384 / NCI NIH HHS
Identifiers: 99900546601901842
Language: English
Resource Type: Journal article