Mitochondrial and microsomal derived reactive oxygen species mediate apoptosis induced by transforming growth factor-β1 in immortalized rat hepatocytes
✍ Scribed by Craig D. Albright; Rudolf I. Salganik; Corneliu N. Craciunescu; Mei-Heng Mar; Steven H. Zeisel
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 202 KB
- Volume
- 89
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Abstract
Transforming growth factor‐β1 (TGFβ1) is a multifunctional cytokine that is over expressed during liver hepatocytes injury and regeneration. SV40‐transformed CWSV‐1 rat hepatocytes that are p53‐defective undergo apoptosis in response to choline deficiency (CD) or TGFβ1, which mediates CD‐apoptosis. Reactive oxygen species (ROS) are essential mediators of apoptosis. We have shown that apoptosis induced by TGFβ1 is accompanied by ROS generation and the ROS‐trapping agent N‐acetylcysteine (NAC) inhibits TGFβ1‐induced apoptosis. While persistent induction of ROS contributes to this form of apoptosis, the source of ROS generated downstream of TGFβ1 is not clear. The mitochondria and the endoplasmic reticulum both harbor potent electron transfer chains that might be the source of ROS essential for completion of TGFβ1‐apoptosis. Here we show that CWSV‐1 cells treated with cyclosporine A, which prevents opening of mitochondrial membrane pores required for ROS generation, inhibits TGFβ1‐induced apoptosis. A similar effect was obtained by treating these cells with rotenone, an inhibitor of complex 1 of the mitochondrial electron transfer chain. However, we demonstrate that TGFβ1 induces cytochrome P450 1A1 and that metyrapone, a potent inhibitor of cytochrome P450 1A1, inhibits TGFβ1‐induced apoptosis. Therefore, our studies indicate that concurrent with promoting generation of ROS from mitochondria, TGFβ1 also promotes generation of ROS from the cytochrome P450 electron transfer chain. Since inhibition of either of these two sources of ROS interferes with apoptosis, it is reasonable to conclude that the combined involvement of both pathways is essential for completion of TGFβ1‐induced apoptosis. J. Cell. Biochem. 89: 254–261, 2003. © 2003 Wiley‐Liss, Inc.