Acute effects of novel selenazolidines on murine chemoprotective enzymes.
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 [2-(2'-hydroxy)phenyl SCA (PhOHSCA) and 2-methyl SCA (MSCA)] and higher [2-cyclohexyl SCA (ChSCA) and 2-oxo SCA (OSCA)] 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.
El-Sayed
Wael M
WM
University of Utah, Department of Pharmacology and Toxicology, Salt Lake City, UT 84112, United States.
Aboul-Fadl
Tarek
T
University of Utah, Department of Pharmacology and Toxicology, Salt Lake City, UT 84112, United States.
Lamb
John G
JG
University of Utah, Department of Pharmacology and Toxicology, Salt Lake City, UT 84112, United States.
Roberts
Jeanette C
JC
University of Wisconsin, School of Pharmacy, Madison, WI 53705, United States.
Franklin
Michael R
MR
University of Utah, Department of Pharmacology and Toxicology, Salt Lake City, UT 84112, United States. Electronic address: mfranklin@alanine.pharm.utah.edu.
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D019610:Cytoprotection / Q000187:drug effects*; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D005979:Glutathione Peroxidase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017279:Selenocysteine / Q000494:pharmacology*; D013997:Time Factors
D015415:Biomarkers; D004798:Enzymes; D011355:Prodrugs; D012333:RNA, Messenger; D017279:Selenocysteine; D005979:Glutathione Peroxidase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D000410:Alanine Transaminase; D004851:Epoxide Hydrolases