Copied and posted my post from FAVC:
This generalized affects of xenobotics on mitochondria, respiratory chain, rising of ROS, Nitric Oxide, etc... could be helped by the Pall's protocol (in the previous post.)* Several posts emphasized the importance of taking anti-oxidants. There is direct correlation with xenobotics depletion of oxidants by multiplying ROS, free radicals.
For some, it may be difficult to take those anti-oxidants, but there are other ways to raise glutathione for instance, or by mild gentle detoxing over a period time that would be useful.
IMHO, damage control concerning the issues of ROS and Nitric Oxide and other free radicals are of paramount importance, for recovery, or at least, prevent further damage.
* Will post about Dr Pall's theory and The NO-ONOO theory under Nitric Oxide thread
Am J Physiol Cell Physiol 293: C12-C21, 2007. First published May 2, 2007;
SPECIAL SECTION ON MITOCHONDRIAL MODELING AND FUNCTIONThe role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topicRoberto Scatena,1 Patrizia Bottoni,1 Giorgia Botta,2 Giuseppe E. Martorana,1 and Bruno Giardina1
1Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Rome; and 2Dipartimento Farmaco Chimico Tecnologico, Università di Siena,
Siena, Italy
Abstract
In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase-{gamma} (pol-{gamma}). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes.
Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers.
The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects.
mitochondrial diseases; nitric oxide; apoptosis; degenerative diseases; free radicals
MITOCHONDRIA CAN REPRESENT a primary or secondary drug target (102, 112). However, some aspects of drug-mitochondria interactions may still be underestimated because of the difficulty in foreseeing and understanding all potential implications of the complex pathophysiology of mitochondria. Insufficient consideration of mitochondrial pharmacotoxicology may also be due to a lack of knowledge about acquired mitochondrial diseases, which are a heterogeneous and growing class of disorders ranging from Type 2 diabetes to neurodegenerative diseases and cancer (30, 32, 105).
A pathogenetic role for mitochondrial dysfunction has been invoked in a vast number of illnesses without sufficient experimental support to precisely establish the molecular pathophysiological mechanisms. Indeed, mitochondrial physiology and pathophysiology are very complex, and the role of the organelles in bioenergetics is strictly
linked to other essential functions such as anabolic pathways, redox balance, cell death and differentiation, and mitosis, along with more specialized cell functions including calcium homeostasis and thermogenesis, reactive oxygen species (ROS) and reactive nitric oxide species signaling, ion channels, and metabolite transporters. The same complexity and heterogeneity can be surmised from the range of congenital mitochondrial diseases, providing further evidence of the difficulty in correctly approaching mitochondrial pathophysiology.
These unique aspects of mitochondria should stimulate us to pay more attention than that usually devoted to both the toxic and therapeutic aspects of the interrelationships between drugs and mitochondria. Moreover, their typical structural and functional characteristics may make mitochondria a valuable target for xenobiotics (30, 32).
Mitochondria: Structure-Function and Pharmacotoxicology Relationships Two main structural and functional aspects of mitochondria should first be considered: the presence of different organelle subcompartments in mitochondria and the fact that mitochondria have their own DNA. Structurally, mitochondria are very diverse across organs and tissues, but all mitochondria contain two lipid bilayer membranes. The outer membrane delineates the organelle and is structurally similar to other cell membranes, being rich in cholesterol and permeable to ions. The inner membrane, which isolates the matrix, is virtually devoid of cholesterol, is rich in cardiolipin (which binds the proteins of the electron transport chain), and is impermeable to ions.
This impermeability accounts for the generation of the electrochemical gradient that supplies the proton motive force for ATP generation. Therefore, the maintenance of the integrity of this inner mitochondrial membrane is critical for mitochondrial function. This typical structure is suitably organized to perform and finely coordinate all of the distinctive activities of mitochondria. In fact, in addition to their critical role in energy generation in eukaryotic cells, mitochondria are also active participants in a variety of tissue-specific metabolic processes, such as urea generation, heme synthesis, and fatty acid beta-oxidation. Mitochondria are able to carry out all of these functions because they are characterized by a unique milieu, with an alkaline and negatively charged interior and a series of specific channels and carrier proteins. Importantly, the complex structure and typical physicochemical characteristics [mainly mitochondrial membrane potential ({Delta}{psi}) and pH {approx} 8] facilitate the selective accumulation of xenobiotics in the matrix and/or the inner mitochondrial membrane by exerting an efficient trap effect (79, 100).
As a consequence, mitochondria can easily accumulate lipophilic compounds of cationic character and, even better, weak acids in their anionic forms. Importantly, for the latter in particular, their undissociated forms can penetrate the inner mitochondrial membrane freely, while their protons dissociate when inside the alkaline matrix, rendering the molecules much less permeant and trapping them inside the organelle (7). Such mitochondrial drug storage may interfere with the determination of pharmacokinetic parameters (distribution volume, plasma concentration, and half-life). Moreover, a vicious circle could then ensue, possibly leading to the progressive accumulation of these acid lipophilic xenobiotics inside mitochondria, damaging their function and permeability properties. Depending on the level and number of mitochondria affected, the cell could go toward a grave deenergization state that in turn can lead to necrosis or more localized damage of a few mitochondria with a collapse of their {Delta}{psi}. The resultant pH modification could reprotonate the xenobiotic, rendering it freely permeant in the cell and capable of entering other mitochondria (91, 92). This process may thus allow a progressive spread of the xenobiotic.
Mitochondria are the only organelles outside of the nucleus that contain DNA. The mitochondrial genome consists of a small circular chromosome that contains a total of 37 genes. Thirteen of these encode proteins that are unique components of the electron transport chain. The remaining genes encode 22 tRNAs and 2 ribosomal RNAs used in the mitochondrial ribosome subunits. The result is that the mitochondrion is fully capable of synthesizing at least some proteins (the remaining proteins are the products of nuclear genes and are synthesized in the cytosol and translocated into the mitochondria). This capability is essential to its function in energy generation, but exposes it to unique risks.
Unlike nuclear DNA, mitochondrial DNA (mtDNA) is not protected by histone proteins. Furthermore, mitochondria are located in close proximity to sites where ROS are routinely generated. However, DNA repair processes are generally less efficient for mtDNA.
As a result, mtDNA is more likely to undergo mutation than nuclear DNA; the mutation rate is estimated to be at least 10–20 times higher (9).
mtDNA can undergo replication and, to a limited extent, base excision repair. Both of these functions reside in a single DNA polymerase, polymerase-{gamma} (pol-{gamma}), in mitochondria (in contrast to nuclear DNA, which is maintained by at least 9 polymerases). Although pol-{gamma} is a nuclear protein, it has no known function other than mtDNA replication, and thus any mutation or inhibition of this enzyme will be manifested only in mtDNA.
All of this underscores the fact that mitochondria are potential primary or secondary targets of xenobiotics and that the interaction of xenobiotics with mitochondria or mitochondrial components (i.e., mtDNA, respiratory chain complexes, biomembranes with their different transporters, or matrix metabolic enzymes) should not always be considered negative. In fact, recent data show that an unexpected therapeutic effect could result from pharmacological modulation of the organelle's activities (30, 32, 79, 91, 92).
Many chemicals are known to interact with mitochondrial molecules (22, 77, 83); however, an in-depth discussion of all the known interactions is beyond the scope of this article and would not be possible because of space constraints. The aim of this review is to discuss the role of mitochondria in general and of their subcompartments in particular in pharmacotoxicology, describing whenever possible the main molecular mechanisms underlying unwanted and therapeutic effects. Such knowledge could stimulate interest in the possible incidence of iatrogenic mitochondriopathies and, moreover, promote a real mitochondrial pharmacology with potential therapeutic applications in a growing number of prominent disease states, including ischemia-reperfusion injury, neurodegenerative diseases, cancer, metabolic syndrome, and hyperlipidemias.
Mitochondria and Drugs: Toxicological Issues Mitochondria play a critical role in supplying the cell with the bulk of its ATP needs via oxidative phosphorylation (oxphos); thus any cell type or tissue with a high aerobic energy requirement is more likely to be affected when this organelle is dysfunctional. In addition, the enzymes necessary for several specialized metabolic processes (fatty acid beta-oxidation, urea synthesis, heme synthesis) reside within the mitochondrial matrix. As a result, tissues that rely heavily on these processes are also frequent targets of mitochondrial toxins.
For these reasons there are numerous common syndromes associated with mitochondrial toxicity
including lactic acidosis, cardiac and skeletal myopathy, peripheral, central, and optic neuropathy, retinopathy, ototoxicity, enteropathy, pancreatitis, diabetes, hepatic steatosis, and hematotoxicity. Combinations of these effects (or different manifestations of toxicity in different individuals treated with the same compound) are not uncommon and are strong indicators that the underlying toxic insult involves mitochondria. Mitochondrial toxicities in general tend to be chronic injuries with somewhat variable manifestations.
Most cells contain a large number of mitochondria that allow for some functional reserve, and cellular injury or dysfunction will occur only when enough mitochondria are irreparably damaged and the cell cannot meet its energy demands. When cells divide, the mitochondria apportionment between them is random ("heteroplasmy"): one daughter cell may contain primarily normal mitochondria while the other gets a disproportionate share of damaged mitochondria, resulting in a patchy distribution of damaged cells within a tissue.
Mitochondrial DNA. mtDNA may be damaged by drugs through different mechanisms.
A well-known exogenous agent capable of oxidatively damaging mtDNA is ethanol (26).
Some drugs can selectively damage mtDNA by inhibiting its synthesis, as has been recently exploited with the introduction of nucleotide reverse transcriptase inhibitors (NRTIs). These compounds are nucleoside analogs that are taken up by cells and sequentially phosphorylated to the active triphosphate form (22, 66). The nucleotide triphosphates can thus be used as substrates by retroviral reverse transcriptase, while their incorporation into the nascent DNA chain results in chain termination.
The triphosphate forms of these analogs have also been shown to be potential substrates for pol-{gamma}, the unique mtDNA polymerase, and can similarly result in chain termination during mtDNA replication (22). Additional effects on mtDNA synthesis result from the fact that the conversion of the monophosphorylated to the triphosphorylated form is extremely inefficient within mitochondria. Consequently, these monophosphorylated forms can build up to high (mM) levels in the mitochondrial matrix and at such high levels can have other effects on mtDNA synthesis.
These include inhibition of the exonuclease function of pol-{gamma} (resulting in decreased replication fidelity) and also, as recently shown with zidovudine, may significantly inhibit thymidine phosphorylation, thus affecting DNA replication by depletion of a necessary substrate (111). This DNA pol-{gamma} dysfunction, which induces a progressive depletion of mtDNA, ultimately interferes with the synthesis of essential proteins of the mitochondrial respiratory chain (MRC) (65, 72).
The consequent disruption of the electron respiratory chain results in reduced ATP synthesis and electron leakage, leading to increased production of free radical species. Enzyme assay and cell culture studies of NRTIs have demonstrated the following hierarchy of mtDNA pol-{gamma} inhibition: zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir (96). In vitro investigations have also documented impairment of mitochondrial adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator. Inhibition of pol-{gamma} and other mitochondrial enzymes can gradually lead to critical mitochondrial dysfunction and cytotoxicity.
The clinical manifestations of NRTI-induced mitochondrial toxicity resemble those of inherited mitochondrial diseases, i.e., hepatic steatosis, lactic acidosis, myopathy, peripheral neuropathy, and, intriguingly, nephrotoxicity. Fat redistribution syndrome, or human immunodeficiency virus (HIV)-associated lipodystrophy, is another side effect attributed in part to NRTI therapy (18). The morphological and metabolic complications of this syndrome are similar to those of the mitochondrial disorder known as multiple symmetric lipomatosis, suggesting that this too may be related to mitochondrial toxicity (59, 65, 117).
Mitochondrial respiratory chain. Drug-induced derangements of the MRC can occur at any of the four protein complexes in the respiratory chain. Effects on complex IV (cytochrome-c oxidase), however, are the most severe because this is the step where oxygen is reduced to water. Inhibition of complex III can also frequently result in the generation of ROS as a consequence of the intrinsic characteristics of the electron transfer process to this complex from reduced ubiquinone
ajpcell.physiology.org/cgi/content/full/293/1/C12