Journal article
α-Hydroxytamoxifen is a substrate of hydroxysteroid (alcohol) sulfotransferase, resulting in tamoxifen DNA adducts
Cancer research (Chicago, Ill.), Vol.58(4), pp.647-653
1998
PMID: 9485016
Abstract
When alpha-hydroxytamoxifen (alpha-OHTAM) was incubated with rat liver hydroxysteroid (alcohol) sulfotransferase a (STa) and 3'-phosphoadenosine 5'-phosphosulfate, (E)-alpha-OHTAM was found to be a better substrate for STa than (Z)-alpha-OHTAM. To explore the formation of tamoxifen (TAM)-derived DNA adducts, DNA was incubated with STa and either (E)-alpha-OHTAM or (Z)-alpha-OHTAM in the presence of 3'-phosphoadenosine 5'-phosphosulfate. Using 32P-postlabeling analysis, the amount of TAM-DNA adducts resulting from (E)-alpha-OHTAM was 29 times higher than that observed with (E)-alpha-OHTAM alone. Using (Z)-alpha-OHTAM and STa, some TAM-DNA adducts were also detected but at levels 6.5 times lower than that observed with (E)-alpha-OHTAM and STa. When compared with standards of stereoisomers of 2'-deoxyguanosine 3'-monophosphate-N2-tamoxifen, the major tamoxifen adduct was identified chromatographically as an epimer of the trans form of alpha-(N2-deoxyguanosinyl)tamoxifen, and the minor adduct was identified as an epimer of the cis form. In the reaction mixture, a conversion from (E)-alpha-OHTAM to (Z)-alpha-OHTAM through the carbocation intermediate was also detected. These results show that sulfation of alpha-OHTAM catalyzed by STa results in the formation of TAM-DNA adducts.
Details
- Title: Subtitle
- α-Hydroxytamoxifen is a substrate of hydroxysteroid (alcohol) sulfotransferase, resulting in tamoxifen DNA adducts
- Creators
- S Shibutani - Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesL Dasaradhi - Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesI Terashima - Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesE Banoglu - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, United StatesM. W Duffel - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.58(4), pp.647-653
- Publisher
- American Association for Cancer Research
- PMID
- 9485016
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 1998
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984303285602771
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