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Acute effects of novel selenazolidines on murine chemoprotective enzymes

jgsun 添加于 2010-10-21 22:12 | 1804 次阅读 | 0 个评论

作者
ELSAYED W, ABOULFADL T, LAMB J, ROBERTS J, FRANKLIN M
摘要
Novel selenazolidines, designed as l -selenocysteine prodrugs and potential cancer chemopreventive agents, were examined for their ability to affect the transcription of murine hepatic chemoprotective enzymes. Compounds investigated were selenazolidine-4( R )-carboxylic acid (SCA) and six 2-substituted derivatives that cover a C log P range of −0.512 to −3.062. Their biological effects were compared with those of l -selenocystine. Gene transcripts were examined 24 h after a single dose, administered i.p. and i.g., and covered a range of chemoprotective enzymes; alpha, mu and pi class glutathione transferases (Gsts), UDP-glucuronosyltransferases (Ugts) 1a1, 1a6, 1a9, and 2b5, glutathione peroxidase 1 (Gpx), thioredoxin reductase (Tr), NAD(P)H-quinone oxidoreductase 1 (Nqo), and microsomal epoxide hydrolase (Meh). When given i.g., 2-butyl SCA (BSCA) resulted in elevations in alpha, mu and pi class Gsts, Ugt1a6, Tr, and Gpx, and 2-phenyl SCA (PhSCA) elevated GstP, Ugt1a9, Tr, Gpx (3 kb), and Meh. Other derivatives with C log P values both lower and higher than BSCA and PhSCA elevated far fewer transcripts; PhOHSCA (Ugt1a1, Gpx), MSCA (Ugt1a1, Meh), ChSCA (Ugt1a1, Ugt1a9), and OSCA (Ugt1a6, Ugt1a9, GstM). When given i.p., the most pervasive transcript changes were parallel increases in Nqo and Tr transcripts which occurred with BSCA, PhSCA, MSCA, and OSCA. PhSCA also increased GstP, and PhOHSCA increased Ugt1a1 and Ugt1a6 levels. Unique among the compounds, PhSCA reduced the transcript levels of GstA, and the 1.6 kb transcript of Gpx although only when given i.p. Neither l -selenocystine nor SCA affected the level of any transcript and no compound altered the amount of Ugt2b5 mRNA. Despite chemical similarity and common ability to potentially serve as a source of l -selenocysteine, each selenazolidine compound appeared to elicit a unique pattern of mRNA responses and by either route of administration, there was no correlation between the magnitude of response of any gene and the calculated C log P values of the organoselenium compounds.
详细资料
- 文献种类: Journal Article
- 期刊名称: Chemico-Biological Interactions
- 期刊缩写: Chemico-Biological Interactions
- 期卷页: 2006年第162卷第1期 31-42页
- ISBN: 0009-2797
学科领域生物医药 » 药学
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