Oguro T, Kaneko E, Numazawa S, Imaoka S, Funae Y, Yoshida T
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan.
J Pharmacol Exp Ther. 1997 Mar;280(3):1455-62.
Both trans- and cis-stilbene oxide (TSO and CSO) markedly induced heme oxygenase-1 (HO-1) at the transcriptional level in rat liver. HO-1 induction 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-1 mRNA. In contrast, pretreatment 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. These findings indicate that the oxidative stress evoked by GSH depletion after the treatment of rats with stilbene oxides could stimulate both HO-1 and c-jun gene expression. Pretreatment with either BSO or PFDA also affected the induction of CYP2B1/2 mRNA and apoprotein by TSO or 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 depletion, but trans-stilbene (TS) failed to elevate HO-1 mRNA under the experimental conditions. In addition, CS increased CYP2B1/2 mRNA, whereas TS did not. These results suggest that CS could be rapidly oxidized 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 TS are attributable to the differential effects on HO and P-450 induction by these compounds. Like other phenobarbital-type P-450 inducers, TSO and CSO also induced CYP2C6 and 3A2 apoproteins in rat liver. Stilbene oxide reduced CYP2E1 mRNA and apoproteins for CYP2E1 and 2C11. All of these findings indicate that stilbene compounds have unique effects on hepatic HO-1 and P-450 regulation in rats.
反式和顺式氧化茋（TSO和CSO）均能在转录水平显著诱导大鼠肝脏中的血红素加氧酶-1（HO-1）。TSO和CSO诱导HO-1之前，肝脏中的谷胱甘肽（GSH）会消耗。用丁硫氨酸亚砜胺（BSO，一种GSH生物合成抑制剂）预处理大鼠，会增强TSO或CSO引起的GSH消耗，并增强HO-1 mRNA的增加。相反，用全氟癸酸（PFDA）预处理可降低肝脏GSH S-转移酶活性，从而防止TSO和CSO介导的GSH消耗，并消除HO-1诱导。此外，TSO和CSO增强了c-jun而非c-fos mRNA，这与HO-1 mRNA的变化平行。这些发现表明，用氧化茋处理大鼠后，GSH消耗引起的氧化应激可刺激HO-1和c-jun基因表达。用BSO或PFDA预处理也会影响TSO或CSO对CYP2B1/2 mRNA和载脂蛋白的诱导，这表明不仅血红素池大小的变化，而且一些其他未知因素可能参与CYP2B1/2和HO-1基因表达的调节。顺式氧化茋（CSO）的母体化合物顺式茋（CS）也会诱导HO-1 mRNA，并伴有肝脏GSH消耗，但在实验条件下反式茋（TS）未能提高HO-1 mRNA。此外，CS增加了CYP2B1/2 mRNA，而TS则没有。这些结果表明CS可被细胞色素P-450（P-450）迅速氧化为CSO，导致肝脏中GSH消耗。CS和TS肝脏代谢途径的这种差异归因于这些化合物对HO和P-450诱导的不同影响。与其他苯巴比妥型P-450诱导剂一样，TSO和CSO也能诱导大鼠肝脏中的CYP2C6和3A2载脂蛋白。氧化茋降低了CYP2E1 mRNA以及CYP2E1和2C11的载脂蛋白。所有这些发现表明，氧化茋化合物对大鼠肝脏HO-1和P-450调节具有独特作用。
