Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 25, 1995 - Issue 10
69
Views
17
CrossRef citations to date
0
Altmetric
Research Article

Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen

, &
Pages 1151-1164 | Received 06 Feb 1995, Published online: 22 Sep 2008
 

Abstract

1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples.

2. Either 150 μM CsA or 50 μM tamoxifen caused approximately 50% loss of HepG2 cell viability. α-Tocopherol (32 μM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S.R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen.

3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation.

4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.