Induction of glutathione-S-transferase mRNA levels by chemopreventive selenocysteine Se-conjugates.

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.

• Authors: Peter A C 't Hoen, Martijn Rooseboom, Martin K Bijsterbosch, Theo J C van Berkel, Nico P E Vermeulen, Jan N M Commandeur
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 63 Issue 10 Pg. 1843-9 (May 15 2002) ISSN: 0006-2952 [Print] England
• PMID: 12034368 (Publication Type: Journal Article)

Chemical References

• RNA, Messenger
• Selenium Compounds
• selenol
• Selenocysteine
• Cytochrome P-450 Enzyme System
• Glutathione Transferase
• Lyases

Topics

• Animals
• Cytochrome P-450 Enzyme System (biosynthesis)
• Enzyme Induction (drug effects)
• Glutathione Transferase (biosynthesis)
• Hepatocytes (drug effects, metabolism)
• Lyases (metabolism)
• RNA, Messenger (biosynthesis, drug effects)
• Rats
• Selenium Compounds (metabolism)
• Selenocysteine (chemistry, pharmacology)
• Tumor Cells, Cultured