Abstract
Several selenocysteine Se-conjugates (SeCys-conjugates) prevent against chemically induced carcinogenesis. Bioactivation to selenols (RSeH) by beta-lyases is thought to be critical, but the mechanism of tumor suppression remains unclear. Induction of phase II biotransformation enzymes is a possible mechanism of chemoprevention. In this study, we evaluated the isoform-selective induction of glutathione-S-transferase (GST) at the mRNA level using a quantitative reverse transcriptase polymerase chain reaction assay. In cultured primary rat hepatocytes and H35 Reuber rat hepatoma cells, SeCys-conjugates time-dependently increased mRNA levels of GST Alpha isoforms and GST Pi, but not of GST Mu isoforms. Se-allyl-L-selenocysteine, the most potent chemopreventive SeCys-conjugate so far known, was also the most active GST inducer. After exposure for 24hr, it elevated GSTA2, GSTA3, GSTA5, and GSTP mRNA levels in primary hepatocytes 3.2+/-0.4-, 1.9+/-0.1-, 4.3+/-0.3-, and 2.9+/-0.3-fold, respectively. Se-allyl-D-selenocysteine was significantly less active, suggesting that stereoselective conversion of SeCys-conjugates to selenols is involved in GST induction. In H35 Reuber hepatoma cells, where conversion of SeCys-conjugates to selenols was 2-6-fold lower than in primary hepatocytes, GST induction was also much lower than in primary hepatocytes. SeCys-conjugates did not induce cytochrome P450 1A1, 2B1/2, or 3A1. This indicates that SeCys-conjugates are monofunctional inducers of phase II biotransformation enzymes. The present results suggest that induction of GST expression contributes to the chemopreventive activity of SeCys-conjugates.
Original language | English |
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Pages (from-to) | 1843-9 |
Number of pages | 7 |
Journal | Biochemical Pharmacology |
Volume | 63 |
Issue number | 10 |
DOIs | |
Publication status | Published - 15 May 2002 |
Keywords
- Animals
- Cytochrome P-450 Enzyme System
- Enzyme Induction
- Glutathione Transferase
- Hepatocytes
- Lyases
- RNA, Messenger
- Rats
- Selenium Compounds
- Selenocysteine
- Tumor Cells, Cultured
- Journal Article