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Yan, 2012 Mitochondrial Dysfunction Induced by Sertraline (Zoloft)


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Toxicol. Sci. (2012) 127 (2): 582-591. doi: 10.1093/toxsci/kfs100 First published online: March 2, 2012
Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent
Yan Li*,
Letha Couch†,
Masahiro Higuchi‡,
Jia-Long Fang† and
Lei Guo†,1
 
Abstract and full free text at http://toxsci.oxfordjournals.org/content/127/2/582.short
 
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.
 

http://toxsci.oxfordjournals.org/content/127/2/582.short

WARNING THIS WILL BE LONG
Had a car accident in 85
Codeine was the pain med when I was release from hosp continuous use till 89
Given PROZAC by a specialist to help with nerve pain in my leg 89-90 not sure which year
Was not told a thing about it being a psych med thought it was a pain killer no info about psych side effects I went nuts had hallucinations. As I had a head injury and was diagnosed with a concussion in 85 I was sent to a head injury clinic in 1990 five years after the accident. I don't think they knew I had been on prozac I did not think it a big deal and never did finish the bottle of pills. I had tests of course lots of them. Was put into a pain clinic and given amitriptyline which stopped the withdrawal but had many side effects. But I could sleep something I had not done in a very long time the pain lessened. My mother got cancer in 94 they switched my meds to Zoloft to help deal with this pressure as I was her main care giver she died in 96. I stopped zoloft in 96 had withdrawal was put on paxil went nutty quit it ct put on resperidol quit it ct had withdrawal was put on Effexor... 2years later celexa was added 20mg then increased to 40mg huge personality change went wild. Did too fast taper off Celexa 05 as I felt unwell for a long time prior... quit Effexor 150mg ct 07 found ****** 8 months into withdrawal learned some things was banned from there in 08 have kept learning since. there is really not enough room here to put my history but I have a lot of opinions about a lot of things especially any of the drugs mentioned above.
One thing I would like to add here is this tidbit ALL OPIATES INCREASE SEROTONIN it is not a huge jump to being in chronic pain to being put on an ssri/snri and opiates will affect your antidepressants and your thinking.

As I do not update much I will put my quit date Nov. 17 2007 I quit Effexor cold turkey. 

http://survivingantidepressants.org/index.php?/topic/1096-introducing-myself-btdt/

There is a crack in everything ..That's how the light gets in :)

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Seems drugs have to build up in the system before they start to damage mitochondria.  If I understand this right. 

 

If this is in the wrong place feel free to move it to where it should be.

 

Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria
This article has been cited by other articles in PMC.
 
Abstract

Mitochondria play key roles in aerobic life and in cell death. Thus, interference of normal mitochondrial function impairs cellular energy and lipid metabolism and leads to the unleashing of mediators of cell death. The role of mitochondria in cell death due to drug hepatotoxicity has been receiving renewed attention and it is therefore timely to assess the current status of this area.

Introduction

Mitochondrial impairment is usually a final event common to pathways leading to necrotic and apoptotic cell death. Therefore, it is important to consider whether drug-induced participation of mitochondria in hepatocellular death is a direct result of drugs acting on these organelles (e.g., drug accumulation, inhibition of electron transport and fatty acid oxidation, or depletion of anti-oxidant defense) or an indirect result ensuing from mitochondrial participation in programs of cell death. Whether these programs lead to necrosis or apoptosis, they are mediated through signaling mechanisms arising at the cell membrane (e.g., death receptors) or in subcellular compartments (e.g., the endoplasmic reticulum or cell nucleus). Evidence for a combination of direct and indirect models in drug toxicity have recently emerged, such that a direct effect of drug or drug metabolite promotes mitochondrial production of reactive oxygen species (ROS), whereas an indirect effect occurs upon the evocation of signal transduction programs that culminate in further loss of mitochondrial function.

In this review Dean Jones describes some of the basic principles about mitochondrial function, redox regulation, and ROS production; John Lemasters offers an overview of mitochondrial permeability transition as a target and executioner of cell death; Derick Han assesses the interplay of signal transduction and mitochondria in the acetaminophen model of drug-induced liver injury (DILI); and Urs Boelsterli describes the threshold hypothesis that may explain the long latency often seen in idiosyncratic DILI.

Non-Equilibrium States of Thiol–Disulfide Systems

Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants; however, the finding that thiols [i.e., glutathione (GSH) and cysteine (Cys)] in plasma are not in redox equilibrium with their disulfide products [i.e., respectively, GSSG and CySS] (12) and that their plasma concentrations are substantially displaced from cellular values (3) has significantly altered concepts of oxidative stress (45). For example, the in vivo “balance” of pro-oxidants and antioxidants cannot be defined by any single entity, such as an equilibrium constant, and our growing knowledge of signaling mechanisms indicates that oxidative stress may be better defined as a disruption of redox signaling, rather than as an imbalance of pro-oxidants and antioxidants (4). The failure of large-scale, double-blind interventional trials with free-radical scavenging antioxidants may likewise reflect an oversimplified therapeutic approach. Thiol–disulfide couples represent key nodes of redox signaling and regulatory mechanisms. Sulfhydryl-containing regulators (e.g., thioredoxins and glutathione) of electron transfer rates can be thought of as biological redox switches and are essential to toxicologic and pathologic mechanisms. The dynamics of non-equilibrium control of redox elements in biologic systems remain a major challenge to our understanding of redox signaling and oxidative stress (6).

An important aspect of redox biology lies in the structures of lipid-containing membranes and multiprotein complexes that function to organize compatible thiol/disulfide couples and orchestrate appropriate redox reactions. The steady-state redox potentials (Eh) of thioredoxin-1, thioredoxin-2, GSH/GSSG, and Cys/CySS couples in mitochondria, nuclei, and secretory complexes, as well as in the extracellular space, are maintained at distinct, disequilibrium values (7). The most highly reducing milieu, promoting the highest rates of electron transfer, is compartmentalized within the mitochondria, which are thus most sensitive to physiologically induced oxidation. In a sense, mitochondria have evolved as compartments that specialize in redox chemistry, and this specialization can make mitochondria selectively vulnerable in pathologic mechanisms.

Mitochondrial Redox Circuits and Thiol-Based Antioxidant Systems

Two types of redox circuits have been distinguished in mitochondria, based upon relative rates of electron transfer (Figure 1(8). High-flux circuits, in which electron transfer rates are a significant fraction of the rate of cellular O2 consumption, include pathways of intermediary metabolism that maintain energy supply. The high-flux circuits are principally responsible for maintenance of the mitochondrial membrane potential and the production of “high-energy” chemicals (e.g., ATP and succinyl CoA) and effective reductants (e.g., NADPH); high-flux circuits thus subserve biosynthetic and detoxification purposes. In contrast, there appear to be a number of low-flux circuits that subserve a regulatory function and are operationally defined as pathways normally having electron transfer rates less than 1% the rate of cellular O2 consumption. The existence of these low-flux circuits has been largely obscured by the concept that mitochondria generate ROS [e.g., superoxide anion (O2•−) and hydrogen peroxide (H2O2)] as a toxic byproduct of aerobic existence. In fact, O2•− and H2O2 appear to be produced by mitochondria regardless of aerobic conditions and may act as essential signaling molecules to coordinate respiratory functions (8). Superoxide, produced under conditions of ample NADH, inhibits aconitase, a key enzyme for controlling NADH generation, and thereby provides a feedback mechanism to control electron flow. At the same time, superoxide activates uncoupling proteins and thereby prevents excessive membrane potential. Superoxide is also a precursor for H2O2, which appears to be a substrate for several mitochondrial proteins, including GSH peroxidase-(GPX)-1 and GPX4, peroxiredoxin-(Prx)-3, Prx5, thioredoxin reductase-2, and forms of GSH transferase(7910); in addition, H2O2 is released by mitochondria and acts as a nuclear signal of NF-κB, Nrf2 and PPAR pathways (1012). (See Figure 1.)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895369/?report=classic

WARNING THIS WILL BE LONG
Had a car accident in 85
Codeine was the pain med when I was release from hosp continuous use till 89
Given PROZAC by a specialist to help with nerve pain in my leg 89-90 not sure which year
Was not told a thing about it being a psych med thought it was a pain killer no info about psych side effects I went nuts had hallucinations. As I had a head injury and was diagnosed with a concussion in 85 I was sent to a head injury clinic in 1990 five years after the accident. I don't think they knew I had been on prozac I did not think it a big deal and never did finish the bottle of pills. I had tests of course lots of them. Was put into a pain clinic and given amitriptyline which stopped the withdrawal but had many side effects. But I could sleep something I had not done in a very long time the pain lessened. My mother got cancer in 94 they switched my meds to Zoloft to help deal with this pressure as I was her main care giver she died in 96. I stopped zoloft in 96 had withdrawal was put on paxil went nutty quit it ct put on resperidol quit it ct had withdrawal was put on Effexor... 2years later celexa was added 20mg then increased to 40mg huge personality change went wild. Did too fast taper off Celexa 05 as I felt unwell for a long time prior... quit Effexor 150mg ct 07 found ****** 8 months into withdrawal learned some things was banned from there in 08 have kept learning since. there is really not enough room here to put my history but I have a lot of opinions about a lot of things especially any of the drugs mentioned above.
One thing I would like to add here is this tidbit ALL OPIATES INCREASE SEROTONIN it is not a huge jump to being in chronic pain to being put on an ssri/snri and opiates will affect your antidepressants and your thinking.

As I do not update much I will put my quit date Nov. 17 2007 I quit Effexor cold turkey. 

http://survivingantidepressants.org/index.php?/topic/1096-introducing-myself-btdt/

There is a crack in everything ..That's how the light gets in :)

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