Hi Lynn, It seems that tamoxifen can be toxic to mitochondria, especially when the respiration is blocked e.g. by myxothiazol. see our publication in Photochemistry and Photobiology 2012, 88: 1016–1022. This is at 24 h following an overnight incubation with ~15 uM Tamoxifen, but could be analogous to a prolonged clinical administration. There is an ongoing research on the matter... Tamoxifen certainly accumulates in the mitochondria as per our results in the above publication, and surprisingly not much elswhere, which of course is compatible with the mitochondrial localization of the ERβ receptors...

Thanks very much Theodossis. I will read the article and reply with any further questions, if I may. I am actually amazed that there is some research on this. That Tamoxifen accumulates in the mitochondria and not much elsewhere is quite serious, considering the implications of that, not only for those with a Mitochondrial Disorders, but for anyone. I will get a handle on the ERb Receptors and will be interested to view pathways/signalling etc in relations to IGF-1, TORC and Apoptosis.

Hi Lyn, one of the researchers from my center have some publication on that subject, her name is Paula I Moreira and she studied the effects of tamoxifen on mitochondria isolated from liver, heart and brain. Maybe you would like to give at look to her papers:

http://www.ncbi.nlm.nih.gov/pubmed/20932907

http://www.ncbi.nlm.nih.gov/pubmed/17397887

http://www.ncbi.nlm.nih.gov/pubmed/16410252

http://www.ncbi.nlm.nih.gov/pubmed/15721176

Good luck with your investigation

Susana

Thank you Susana. Appreciated. Will check your colleagues' papers .

Thankyou Theodossis and Susana. Your Article Theodossis was excellent and I was pleased to see some extrapolation of your data and hypotheses to human dosage of TAM and it effects. I was curious if Complex I & III of mitochondria would also be inhibited via ERbeta in other cell types, and note that your in vivo human study with current therapeutic doses of Tamoxifen were 40-fold increased in the liver compared with the plasma levels. I also note from one of Paula Moreira's Papers that Tam & E2 interact with the Flavin site of Complex I leading to mitochondrial failure. Other studies have also demonstrated deleterious interaction with Complex II (also with key Flavin bifactors for enzymatic function of fatty acid oxidation). So, all in all, not looking good for mitochondria elsewhere in the body, especially liver. whilst clearly the mitochondria are the ultimate pathway through which TAM causes apoptosis and destruction of breast tumor cells. It is my hypothesising (without any data) that the oestrogen antagonist component of TAM is acting by the ERbeta in mitchondria and possibly the ERalpa is working in concert with IGF-1 in liver(and/or locally in breast cells and elsewhere) to reduce tumour cell growth - possibly via IGF-1 (suppressed by oestrogen) by JAK/STAT pathways. Search of scientific literature continues!

Once again, thanks to you both for directing my search of the Literature. Gaining a reasonable grasp and understanding of ER alpha & Beta and the uniqueness of TAM as estrogen agonist and antagonist and its pathways in various tissue/cell lines. I would like to share a reference with you, anyone else who is interested and especially to Oncologists, Physicians and Pharmacists regarding the toxicity and pathway of TAM on the mitochondria. Whilst many drug categories are contraindicated in Mitochondrial Disorders I was somewhat shocked and unaware that TAMOXIFEN is on the small list in the "Black Box" category, along with the better known Amioderone and Valproate.

Begriche,K et al. "Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver" Journal of Hepatology 2011 vol.54:773-794