INDUCTION OF HEPATIC HEME OXYGENASE AND CHANGES IN CYTOCHROME P-450S IN RESPONSE TO OXIDATIVE STRESS PRODUCED BY STILBENES AND STILBENE OXIDES IN RATS

Bath trans- and cis-stilbene oxide (TSO and CSO) markedly induced heme oxygenase-1 (HO-1) at the transcriptional level in rat liver. HO-1 in duction by TSO and CSO was preceded by glutathione (GSH) depletion in the liver. Pretreatment of rats with buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis, enhanced GSH depletion evoked by either TSO or CSO and augmented the increase in HO-I mRNA. In contrast, pret reatment with perfluorodecanoic acid (PFDA), which reduced hepatic GSH S-transferase activity, prevented TSO- and CSO-mediated GSH depletion and abolished HO-1 induction. In addition, TSO and CSO enhanced c-jun but not c-fos mRNA, which is in parallel with the HO-1 mRNA change. T hese findings indicate that the oxidative stress evoked by GSH depleti on after the treatment of rats with stilbene oxides could stimulate bo th HO-1 and c-jun gene expression. Pretreatment with either BSO or PFD A also affected the induction of CYP2B1/2 mRNA and apoprotein by TSO o r CSO, suggesting that not only the change of heme pool size but also some other unknown factor or factors may be involved in the regulation of the CYP2B1/2 and HO-1 gene expression. cis-Stilbene (CS), a parent compound of CSO, also induced HO-1 mRNA, together with hepatic GSH de pletion, but trans-stilbene (TS) failed to elevate HO-1 mRNA under the experimental conditions. In addition, CS increased CYP2B1/2 mRNA, whe reas TS did not, These results suggest that CS could be rapidly oxidiz ed by cytochrome P-450 (P-450) to CSO, leading to GSH depletion in the liver. Such differences in the hepatic metabolic pathways of CS and T S are attributable to the differential effects on HO and P-450 inducti on by these compounds, Like other phenobarbital-type P-450 inducers, T SO and CSO also induced CYP2C6 and 3A2 apoproteins in rat liver. Stilb ene oxide reduced CYP2E1 mRNA and apoproteins for CYP2E1 and 2C11. All of these findings indicate, that stilbene compounds have unique effec ts on hepatic HO-1 and P-450 regulation in rats.