Major differences among chemopreventive organoselenocompounds in the sustained elevation of cytoprotective genes.
Cytoprotective enzyme elevation through the nuclear erythroid 2 p45-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1/antioxidant response element pathway has been promulgated for cancer prevention. This study compares the redox insult and sustained cytoprotective enzyme elevation by organoselenocompounds and sulforaphane (SF) in lung cells. SF elicited a rise in reactive oxygen species (ROS) and drop in glutathione (GSH) at 2 h; nuclear accumulation of Nrf2 at 4 h; and a GSH rebound and elevation in NAD(P)H quinone oxidoreductase (NQO1), thioredoxin reductase (TR1), and glutamate-cysteine ligase (GCL) at 24 h. Selenocystine (SECY) elicited a similar 24 h response, despite lesser earlier time-point changes. 2-Cyclohexylselenazolidine-4-carboxylic acid effects were similar to SECY's but with a larger Nrf2 change and the largest 24 h increase in GSH, GCL, TR1, and NQO1 of any compound investigated. Selenomethionine elicited a similar acute rise in ROS, but lesser depletion of GSH, no 4 h increase in nuclear Nrf2, only minor 24 h elevations in TR1 and NQO1, and a GCL elevation insufficient to elevate GSH.
Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, UT 84112, USA.
Robyn L
RL
Poerschke
Michael R
MR
Franklin
Andrea H
AH
Bild
Philip J
PJ
Moos
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D061745:Antioxidant Response Elements; D002460:Cell Line; D019610:Cytoprotection; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D017879:Isothiocyanates; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D021381:Protein Transport / Q000187:drug effects; D017279:Selenocysteine / Q000494:pharmacology*; D012645:Selenomethionine / Q000494:pharmacology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
C578079:2-cyclohexylselenazolidine-4-carboxylic acid; D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016566:Organoselenium Compounds; D053244:Osteoprotegerin; D013454:Sulfoxides; C506030:TNFRSF11B protein, human; D013861:Thiocyanates; D017279:Selenocysteine; D012645:Selenomethionine; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005721:Glutamate-Cysteine Ligase; C016766:sulforaphane; D005978:Glutathione