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OtherTOXICOLOGY

Induction of Hepatic Heme Oxygenase and Changes in Cytochrome P-450s in Response to Oxidative Stress Produced by Stilbenes and Stilbene Oxides in Rats

Takiko Oguro, Eiko Kaneko, Satoshi Numazawa, Susumu Imaoka, Yoshihiko Funae and Takemi Yoshida
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1455-1462;
Takiko Oguro
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Eiko Kaneko
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Satoshi Numazawa
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Susumu Imaoka
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Yoshihiko Funae
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Takemi Yoshida
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Abstract

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 theHO-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 andHO-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.

Footnotes

  • Send reprint requests to: Takiko Oguro, Ph.D., Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan. E-mail:oguro{at}pharm.showa-u.ac.jp

  • Abbreviations:
    HO
    heme oxygenase
    TSO
    trans-stilbene oxide
    CSO
    cis-stilbene oxide
    TS
    trans-stilbene
    CS
    cis-stilbene
    GSH
    glutathione
    ALAS
    δ-aminolevulinic acid synthetase
    P-450
    cytochrome P-450
    PFDA
    perfluorodecanoic acid
    BSO
    buthionine sulfoximine
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    SDS
    sodium dodecyl sulfate
    AP-1
    activator protein-1
    • Received July 9, 1996.
    • Accepted November 25, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherTOXICOLOGY

Induction of Hepatic Heme Oxygenase and Changes in Cytochrome P-450s in Response to Oxidative Stress Produced by Stilbenes and Stilbene Oxides in Rats

Takiko Oguro, Eiko Kaneko, Satoshi Numazawa, Susumu Imaoka, Yoshihiko Funae and Takemi Yoshida
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1455-1462;

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OtherTOXICOLOGY

Induction of Hepatic Heme Oxygenase and Changes in Cytochrome P-450s in Response to Oxidative Stress Produced by Stilbenes and Stilbene Oxides in Rats

Takiko Oguro, Eiko Kaneko, Satoshi Numazawa, Susumu Imaoka, Yoshihiko Funae and Takemi Yoshida
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1455-1462;
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