4 Medication-induced mitochondrial damage
Mitochondrial dysfunction is increasingly implicated in the
etiology of drug-induced toxicities, but mitochondrial toxicity
testing is still not required by the US FDA for drug
approval [62]. Mitochondria can be damaged both directly
and indirectly by medications (Table 5). Medications can
directly inhibit mtDNA transcription of ETC complexes,
damage through other mechanisms ETC components, and
inhibit enzymes required for any of the steps of glycolysis
and b-oxidation. Indirectly, medications may damage mitochondrial
via the production of free radicals, by decreasing
endogenous antioxidants such as glutathione and by depleting
the body of nutrients required for the creation or proper
function of mitochondrial enzymes or ETC complexes.
Damage to mitochondria may explain the side effects of
many medications.
Barbituates were the first drugs noted in vitro to inhibit
mitochondrial respiration by inhibiting NADH dehydrogenase,
which is situated at complex I of the ETC [63]. This
same mechanism also explains how rotenone caused mitochondrial
damage, thereby making it a useful drug inducing
and studying Parkinson's disease-like symptoms in animal
models [63]. Drugs and some endogenous compounds can
sequester CoA (aspirin, valproic acid), inhibit mitochondrial
b-oxidation enzymes (tetracyclines, several 2-arylpropionate
anti-inflammatory drugs, amineptine, and tianeptine),
or inhibit both mitochondrial b-oxidation and oxphos
(endogenous bile acids, amiodarone, perhexiline, and
diethylaminoethoxyhexestrol) [64]. Other substances
impair mtDNA transcription such as INF-alpha (INF-a) or
mtDNA replication (dideoxynucleosides) [64]. In severe
cases impairment of energy production may contribute to
liver failure, coma, and death [64].
Many psychotropic medications also damage mitochondrial
function. These include antidepressants (amitriptyline
(Lentizolm), amoxapine (Asendism), citalopram (Cipramilm),
fluoxetine (Prozacm, Symbyaxm, Sarafemm, Fontexm, Foxetinm,
Ladosem, Fluctinm, Prodepm, Fludacm, Oxetinm, Seronilm,
Lovanm)), antipsychotics (chlorpromazine, fluphenazine,
haloperidol, risperidone, quetiapine, clozapine, olanzapine),
dementia medications (galantamine (Reminylm),
tacrine (Cognexm)), seizure medications (valproic acid
(Depaconm, Depakenem, depakene syrup, Depakotem, depakote
ER, depakote sprinkle, divalproex sodium)), mood stabilizers
such as lithium, and Parkinson's disease medications
such as tolcapone (Tasmarm, entacapone (COMTanm also in
the combination drug Stalevom)) and benzodiazepines (Diazepamm,
Alprazolamm) [63–73, 91, 92].
Adverse effects of the nucleoside reverse transcriptase
inhibitor (NRTI) class of medications, including zidovudine
(ZDV), didanosine (ddI), zalcitabine (ddC), lamivudine
(3TC), stavudine (D4T), and abacavir (ABC), result from
decreased mitochondrial energy-generating capacity [35].
The underlying mechanism for this is via the inhibition of
DNA polymerase-c, the only enzyme responsible for
mtDNA replication [74]. Inhibiting polymerase-c can lead
to a decrease in mtDNA, the 13 subunits of the mitochondrial
ox-phos system and cellular energy production [35,
74]. NRTI-induced mitochondrial dysfunction explains
many adverse reactions caused by these medications
including polyneuropathy, myopathy, cardiomyopathy, steatosis,
lactic acidosis, pancreatitis, pancytopenia, and proximal
renal tubule dsyfuntion [74].
Acetaminophen (paracetamol, N-acetyl-p-amino-phenol),
the active ingredient in Tylenolm and more than 100
different products, is the leading cause of drug-induced
liver failure in the US [93]. Each year more than 450 deaths
are caused by acute and chronic acetaminophen toxicity
[93]. Acetaminophen is metabolized in the liver primarily
by the cytochrome P450 (CYP) isoenzyme CYP2E1 [94].
When acetaminophen passes through the CYP2E1 enzyme
it is metabolized to N-acetyl-p-benzoquinone-imine
(NAPQI), a toxic intermediate that is subsequently reduced
and conjugated with glutathione before the final substrate
is excreted in the urine [94]. Therefore, the earliest effect of
acetaminophen metabolism is a depletion of hepatic glutathione,
the accumulation of free radicals, and decreased
mitochondrial respiration [95]. Since glutathione depletion
is a mechanism by which acetaminophen causes hepatocellular
necrosis, it is not surprising that the antidote for acetaminophen
poisoning is N-acetylcysteine (NAC), which
increases glutathione [96, 97].
Mechanisms of mitochondrial damage and tissues
affected differ between medications. For example, valproic
acid depletes carnitine [75] and decreases b-oxidation in
the liver [64], thereby contributing to steatosis [64]. The
antipsychotic medications chlorpromazine, fluphenazine,
haloperidol, risperidone, quetiapine, clozapine, and olanzapine
inhibit ETC function [63, 65–68]. The anxiety mediation
Diazepamm was shown to inhibit mitochondrial function
in rat brain, while Alprazolamm does so in the liver [73,
92].
)?
