Science...Mitochondrial Dysfunction Induced by Sertraline (Zolfot)

[btdt]

Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent

1. Yan Li*, 
   
2. Letha Couch†, 
   
3. Masahiro Higuchi‡, 
   
4. Jia-Long Fang† and 
   
5. Lei Guo†,1
   

+Author Affiliations

1.  ^*Division of Genetic and Molecular Toxicology and
   
2.  ^†Division of Biochemical Toxicology, National Center for Toxicological Research/U.S. FDA, Jefferson, Arkansas 72079
   
3.  ^‡Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
   

1. ↵1To whom correspondence should be addressed at Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), Food and Drug Administration (FDA), HFT-110, 3900 NCTR Road, Jefferson, AR 72079. Fax: (870) 543-7136. E-mail: lei.guo@fda.hhs.gov.
   

• Received January 25, 2012.
  
• Accepted February 24, 2012.
  

Abstract

Sertraline, a selective serotonin reuptake inhibitor, has been used for the treatment of depression. Although it is generally considered safe, cases of sertraline-associated liver injury have been documented; however, the possible mechanism of sertraline-associated hepatotoxicity is entirely unknown. Here, we report that mitochondrial impairment may play an important role in liver injury induced by sertraline. In mitochondria isolated from rat liver, sertraline uncoupled mitochondrial oxidative phosphorylation and inhibited the activities of oxidative phosphorylation complexes I and V. Additionally, sertraline induced Ca²⁺-mediated mitochondrial permeability transition (MPT), and the induction was prevented by bongkrekic acid (BA), a specific MPT inhibitor targeting adenine nucleotide translocator (ANT), implying that the MPT induction is mediated by ANT. In freshly isolated rat primary hepatocytes, sertraline rapidly depleted cellular adenosine triphosphate (ATP) and subsequently induced lactate dehydrogenase leakage; both were attenuated by BA. Our results, including ATP depletion, induction of MPT, inhibition of mitochondrial respiration complexes, and uncoupling oxidative phosphorylation, indicate that sertraline-associated liver toxicity is possibly via mitochondrial dysfunction.

Key words

• sertraline
  
•  
  
• liver toxicity
  
•  
  
• mitochondrial dysfunction
  
• rat primary hepatocytes
  
•  
  
• isolated liver mitochondria
  

• Published by Oxford University Press 2012.
  

Articles citing this article

• 
  
  Sertraline, an Antidepressant, Induces Apoptosis in Hepatic Cells Through the Mitogen-Activated Protein Kinase PathwayToxicol Sci (2014) 137 (2): 404-415
  
  
  
  

  • Abstract
    
  • Full Text (HTML)
    
  • Full Text (PDF)
    
  
  
  

http://toxsci.oxford...127/2/582.short

[btdt]

Trying to keep mitochondrial pages together. 

http://www.badscience.net/2014/03/statins-have-no-side-effects-what-our-study-really-found-its-fixable-flaws-and-why-trials-transparency-matters-again/

 

this I found in a talk about trials.. 

particularly relating to statin drugs damaging mitochondria but I have already found a many antidepressants on the list of drugs that damage mitochondria... this explains a bit about how the drugs damage mitochondria and the results. 

 

"

1. FloxieHope said,

   April 3, 2014 at 11:00 pm

   When examining Statins, it should be noted that they have been shown to damage mitochondria. Article – www.ncbi.nlm.nih.gov/pmc/articles/PMC2849981/. Mitochondrial damage can account for all of the relevant adverse effects of statins – muscle weakness and damage, loss of memory/cognitive function, diabetes, depletion of glutathione, etc. An interesting feature of mitochondrial injury is that a threshold of damage must be reached before a disease state results (as described in this article – www.ncbi.nlm.nih.gov/pmc/articles/PMC2895369/?report=classic). So, if your study period isn’t long enough, statins truly will have the same number of adverse effects as sugar pills because in a short period of time, the subjects have not crossed their tolerance threshold for mitochondrial damage and no disease state (or AEs) have manifested. It is only with prolonged exposure to mitochondrial damaging chemicals, like statins, that adverse effects manifest.

   If you don’t design your study of mitochondrial damaging drugs to take into account how mitochondria react to assaults – with an initial adaptive response followed by a toxic response (as the peroxynitrite cycle is induced), your results don’t actually say anything notable. If you design your study to take into account the tolerance threshold feature of mitochondria, and the odd delayed response to toxic stimuli that they often display, you will likely find that statins are quite a bit more dangerous than sugar pills.

   I certainly understand that many research scientists don’t have the time or funding to do long-term studies. But don’t worry – the long-term studies are being done – they’re just being done on the population at large. Hence the reason that it is so important to listen to patients who experience adverse effects of drugs over a long period of time.

   Unfortunately, mitochondrial damage is very difficult to fix and stopping treatment with the mito damaging drug does not necessarily stop the mitochondria from continuing to produce damaging ROS (like peroxynitrite) that continue to do damage long after the drug is metabolized.

   ROS produced in damaged mitochondria are associated with every chronic disease there is. You, and all the other MDs out there may want to consider that chronic disease may be the result of these drugs that are tossed about like candy because they have no adverse effects in the short term, and the long-term effects are dismissed because patient reports are “anecdotal.”"

[btdt]

same link as above 

"

1. David Bailey said,

   April 4, 2014 at 4:16 pm

   FloxieHope,

   Thanks for your observations, because I think it is important to try to make sense of the experiences of many statin users. Although statin effects don’t seem to dissipate completely immediately (mine took about 9 months), the stories (anecdotes?) of many people on Dr Kendrick’s site all seem to confirm that thankfully the effects do reverse.

   Moreover, statins block a synthetic pathway that produces more than just cholesterol, and indeed cholesterol is used throughout the body! Dr Kendrick points out that the ‘normal’ level of cholesterol in humans was determined in a very strange way, and using this as a target figure may be quite harmful."

It may be worth taking a look to see what else this Dr Kendrick has to say.... now I am curious. 

[btdt]

http://www.ccjm.org/content/68/7/625.full.pdf

Mitochondrial cytopathy in adults:

What we know so far

"Mitochondrial diseases may also arise

from processes other than germline mutations

in mtDNA. A case of a somatic (acquired)

mutation causing mitochondrial disease was

recently reported.

 

I found this to be a vary informative read.  I would have posted more but for some reason the copy function is suddenly malfunctioning so see the link and read it for yourself.  I think it uncanny how many of the symptom listed there easily explain some of the worst withdrawal cases I have read and about over the years on sites like this much of it I have lived myself.  Recovery...is also interesting could well be the mitochondria have a way of repairing it self to a certain extent if the damage is drug induced and not genetic... could be as the study of this is in its infancy ... there is a long way to go. 

[westcoast]

http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2895%2900672-9/references

 

I was looking into movement disorders and came across this. I get the feeling Japanese science is more open-minded than US stuff.

 

Previous studies have shown an association between low serum cholesterol concentration and suicide; however, conflicting results have also been reported. To examine this potential association, cholesterol levels in 99 patients admitted to an emergency ward following an attempted suicide were compared with those in 74 nonsuicidal psychiatric inpatients, and those in 39 psychiatrically normal individuals with accidental injuries. Cholesterol concentrations in suicide attempters were found to be significantly lower compared with both psychiatric and normal controls, when sex, age, psychiatric diagnosis, and physical conditions (serum total protein and red blood cell count) were adjusted for. This significant relationship was observed in mood disorders and personality or neurotic disorders, but not in schizophrenia spectrum disorders. These results support the previous claim that lower cholesterol level is associated with an increased risk of suicidal behavior.

 

Hiroshi Kunugi

,

Noriyoshi Takei

,

Hiroko Aoki

,

Shinichiro Nanko

Received: June 13, 1995; Received in revised form: December 13, 1995;

[btdt]

If you were to check the spacedoc.com site a retired NASA doctor terribly affected by statin drugs there is a lot on mitochondria damage also the brain needs cholesterol to function right... as one of the links above shows it could be our needs for cholesterol differ.. we are not all the same. 

[nz11]

Recovery...is also interesting could well be the mitochondria have a way of repairing it self to a certain extent if the damage is drug induced and not genetic.

I hope there is some truth in this ...i can remember saying once at pp that i reckon the mitochondria is impaired.

[btdt]

according to the space doc site CoenzymeQ10 helps to heal mitochondria

[solida]

Hi,it is interesting because last week there was an report on German TV about people who suffered severe trauma.

They were tested before and after therapy-when they were completely healed.

 

In the state of trauma they showed all lower cholesterol and  a change in their genes.

 

After healing the cholesterol and even the genes changed...so what is the chicken and was is the egg?

 

solida

[btdt]

It would depend on which type of genes.. I am not sure how genes relate to mitochondria