Toxicity of a drug or any other chemical that enters living organism, stems from intervention of that chemical into normal biochemical processes, altering them, changing their efficiency or speed, blocking certain biochemical pathways or starting another ones. This changes functional condition of the cell, and, if especially important processes are blocked or altered, cell may be damaged, its abilities to grow and reproduce may be altered, or even cell death may occur due to altered biochemical processes.
Toxic impact of a chemical may result from its ability to bind with certain molecules (proteins, DNA, lipids etc. ), changing their conformation, altering properties or decreasing activity. Sometimes DNA became target of a toxic agent directly (Berdis, 2008, p. 8253). These compounds modify DNA structure or break chemical bonds between nucleotides, thus causing single-or double-stranded breaks in DNA structure. If these breaks are multiple, some of them may be impossible to repair and cellular DNA will be damaged permanently. This will result in mutation.
If this irreparable break will occur in a sequence encoding for a vitally important protein, this mutation will kill the cell or its direct descendants. Otherwise mutation may lead to disease caused by malfunction or absence of protein encoded in a broken region of DNA. Broken DNA strand may be repaired incorrectly. This also will be a mutation and, if incorrect reparation will result in changed structure and efficiency of encoded protein, may also cause disease due to malfunction or dysfunction of that protein. Other way of toxic impact on DNA is indirect one.
Toxic agents may influence enzymes that take part in processes of transcription and translation, in DNA reparation and replication (Berdis, 2008, p. 8253). These processes are very complicated and multistaged, and many enzymes are involved in each stage. Altering or damaging every single enzyme involved can cause entire process to fail. When replication process fails, cell division process becomes impossible. Failed reparation causes increased susceptibility of affected cells to mutagenic factors as errors and minor damages to DNA tend to accumulate and process of repairing these errors is blocked to the certain extent.
Failed transcription or translation result usually in cell death as no new proteins and RNA can be produced to satisfy needs of a cell. A good example of indirect DNA affection is topoisomerase activity inhibition: “Agents such as etoposide inhibit the activity of topoisomerase, an enzyme that resolves the “knots” in DNA formed during replication (4). Inhibition of this enzyme causes apoptosis by creating single- and double-stranded DNA breaks that interrupt the continuity of DNA synthesis. ” (Berdis, 2008, p. 8253-8254).
Proteins become targets of external chemicals more often than DNA. It is logical as far as DNA is stored in the nucleus and protected by proteins of different kinds as well as by nuclear envelope, whereas proteins are ever-present in a living cell and perform a plethora of different functions, including receptor functions of external cellular plasma membrane, where contact with external chemicals is most likely to occur. Most direct and destructing impact on proteins is direct modification of certain amino-acids that are included into the primal structure of that protein.
This direct modification may be performed in a way of covalent binding of external chemical to an amino-acid (Liebler, 2008, p. 117). This results in irreversible conformational changes of a protein containing modified amino-acids, as the bond between amino-acid and modifying agent is as strong as peptide bonds and cell usually has no enzymes to break such bonds. Conformational change of a protein renders it impossible to perform its functions. The more important protein was affected in this way, the more overtly it will impact the cell.
If that protein was of high importance to the organism, e. g. cytochrome P450 of the liver cells, entire organism will be affected by the modification and malfunction of that enzyme. Another way of influence on proteins is non-covalent interaction between protein and chemical. These non-covalent interactions may take form of competition between the chemical and original substrate of an enzyme and thus decrease activity of said enzyme. External chemical may block active center of an enzyme by non-covalent means. This, again, will decrease enzymatic activity of that protein.
Chemical can also interact with an enzyme in a way called allosteric interaction, binding through non-covalent means to a regulative site of a protein and thus changing conformation of an active center of an enzyme, partially or totally altering its activity. Enzymatic activity could be either increased or decreased in every particular occasion depending on type of protein and chemical involved. Impact of thus altered enzymatic activity also depends of initial activity and functions of an enzyme affected and importance of these functions to the cell and organism survival.
Many enzymes and proteins exist in several more or less similar forms in different people among the population of a region. These isoforms are caused by mutations that have caused substitution of a single amino-acid which did not resulted in significant conformational changes of a protein. Such isoforms may perform functions of that protein with more or less unchanged efficiency, but due to substitution some isoforms may appear more susceptible to modifications of other types of influence by certain chemicals.
Existence of several isoforms of a protein creates a phenomenon of individual susceptibility to certain drugs. Chemical that is not intended to cause toxicity in general population may behave as toxicant in an individually susceptible organism. Certain drugs and chemicals indirectly alter metabolism of lipids through influence on activity of enzymes that catalyze reactions of lipid synthesis, cleavage and transformation. Owczarek, Jasinska & Orszulak-Michalak (2005) stated:
Several mechanisms are supposed to contribute to pathogenesis of statin-induced muscle injuries, and inhibition of (HMG-CoA) reductase pathway seems to be one of them. Impairment of protein synthesis … is also supposed to contribute to statin myotoxic effect. This effect probably results from the blockade of farnesyl pyrophosphate production, geranylgeranyl pyrophosphate and their metabolites, but not inhibition of squalene or cholesterol synthesis pathway. (p. 28) Drugs are intended to influence biochemical processes of the cells.
Some drugs influence single enzyme only that is responsible for highly specific reaction in cells, and therefore these drugs have highly specific effect on the organism. But more often than not drug influences several reactions in different ways, or could affect not exclusively enzymes, but other organic molecules, like DNA or lipids, too. This causes unexpected or inevitable side effects, that are often rather adverse. In certain cases adverse effects may be so intense and dangerous that it leads to rejection of drug causing such effects by patients and physicians alike.
Among the examples of adverse effects of drugs is the effect of D-penicillamine, according to Owczarek et al. (2005): D-penicillamine induces a variety of antibodies, especially anti-AchR (acetylcholine receptor) antibody which results in immune system-mediated complications including polymyositis, systemic lupus erythematosus, nephritis, scleroderma and iatrogenic myasthenia gravis. Moreover, at high doses, it impairs neuromuscular transmission by inhibiting release of Ach and blocking calcium entry at the motor nerve terminal, especially if given parenterally.
(p. 23-24). Reactivating influence on antibodies and receptors is not the only way drugs may cause adverse effects. Steroids may cause inhibition of protein synthesis: “The main inhibitory mechanism includes the impaired regulation of the activity of factors involved in peptide initiation” (Owczarek et al. , 2005, p. 27). Also steroids “are supposed to inhibit antiapoptotic effects of IGF-I by reducing its expression [and] increase the cytoplasmic protease activity in muscles, leading to myofibrillar destruction” (Owczarek et al. , 2005, p. 27).
These are mechanisms of steroids responsibility for development of chronic myopathies due to gradual destruction of myofibrils. Additionally, steroids decrease activity of glutamine synthetase and glycogen phosphorylase. These facts give more broad perspective on effects of a drug on multiple protein targets producing overtly adverse effects. Specific toxicity of drugs is rather widespread phenomenon. Adverse effects of drugs on organ of hearing (ototoxicity), organs of vision (ocular toxicity) or olfactory organs (olfactory toxicity) were reported repeatedly.
Some of these effects are mild and transient, whereas other affect life and health of patients more severely, sometimes crippling them, and remain for long time or even forever. Over 500 medications are known that can cause different early symptoms of specific toxicity to organ of hearing, and no less than 740 are reported as potentially or proved of being ototoxic (Bauman, 2006). Ototoxicity is not limited to manifestations of affected hearing – ototoxic drugs may cause various symptoms of different origin. According to Bauman (2006), “average ototoxic drug exhibits about 3. 5 ototoxic symptoms”, and these symptoms are:
Signs of cochlear affection (tinnitus, or “ringing in the ear”, loss or distorted hearing, auditory hallucinations, hyperacusis and feeling of fullness in the ears), symptoms of vestibular apparatus affection (dizziness, vertigo, ataxia, nystagmus, labyrinthitis, loss of balance/equilibrium disorders, oscillopsia, emotional problems, fatigue, memory problems, muscular aches and pains, nausea, visual problems, vomiting, vague feelings of unease), central nervous system side effects (disorders of processing audial signals in the brain cortex – failed recognition of previously familiar sounds) and symptoms of outer or middle ear damage (ceruminosis, ear pain, otitis externa and media) (Bauman, 2006). Certain ototoxic drugs, such as aminoglycosides, may interact synergistically with exposure to noise (Mills & Going, 1982, p. 125).
Insignificant damage to the organ of Corti done by the drug is synergistically added to insignificant damage done by the noise, and more than 80% of receptor cells (or hair cells) could be destroyed as a result of such synergy (Mills & Going, 1982, p. 125). Ototoxic effects manifested in loss or altered hearing or balance, i. e. symptoms of toxic damage done to the cochlea or vestibular apparatus, are caused by destruction of hair cells in the organ of Corti or vestibular system channels. Symptoms like nausea, vomiting and vertigo, along with muscular aches, memory and emotional problems are likely to be secondary due to confusion of the brain by discoordinated signals or due to overwork of the brain and muscles that constantly and consciously maintain balance of the body. Ocular toxicity may arise as an adverse effect of systemic drug therapy.
Even common drugs used at therapeutic doses can trigger hypersensitivity reactions resulting in severe adverse effects on eyes: “Hypersensitivity reactions are common with aspirin taken at therapeutic dosage levels, producing angioneurotic oedema, erythema multiforme, haemorrhagic vasculitis as well as toxic epidermal necrolysis” (Spiteri & James, 1983, p. 343). Sanford-Smith reported transient myopia after intake of aspirin (1974), and development of conjunctivitis, corneal ulceration, perforation and secondary glaucoma were reported by Sainami and Balsara (1970). Almost every part of the organ of vision may become target of toxic affection. Conjunctive, cornea, lacrimal glands, lens and retina, optic nerve and oculomotor muscles may be affected, and intraocular pressure may be altered by certain drugs (Spiteri & James, 1983).
Among the pathological conditions that may arise due to drug toxicity, are “dry eye syndrome”, deposits on the cornea, toxic cataracts, retinopathies, papilloedema, optic neuritis and accompanied vision disorders. Affection of oculomotor muscles result in nystagmus, weak convergence and weak accomodation. Altered intraocular pressure also affects accomodation, decreases clearness and accuracy of vision (Spiteri & James, 1983). In most severe cases complete loss of vision may occur. This loss could be transient or, if damage to the ocular structures is significant, vision can be lost permanently. An example of irreversible retinal and pupillary changes due to acute quinine poisoning is reported by Bacon, Spalton & Smith (1988).
Toxicity to the olfactory organ may arise from direct impact of drug on olfactory mucosa and partial destruction or inactivation of sensory cells or deactivating influence on synaptic contacts between receptors and sensitive neuron. Another source of toxicity is drug delivered to olfactory mucosa through bloodstream. These changes, functional at first, quickly become structural and thus become irreversible, resulting in decreased olfactory sensitivity or even to destroyed sense of smell – anosmia (Wood, 1978). Mechanisms involved in development of toxicity to sensory organs in general are based on influence on cellular and extracellular proteins.
Whether through direct modifications of structure or through altering enzymatic activity through allosteric interactions, drugs affect cells changing their performance and triggering pathological changes in cells and tissues. Modifications of extracellular proteins can lead to change of their ability to perform functions these proteins were initially supposed to perform, and thus to changes of properties of intercellular matrix. Certain drugs may change properties of antibodies causing them to misdiscriminate internal targets as intruders and thus provoke autoimmune pathologies. Direct and indirect impact on DNA is unlikely to be involved in mechanisms of drug toxicity to sensory organs.
This mechanism is often the main for malignant cells formation, and sometimes malignization occurs under influence of the certain drug, but this has little to do with sensory toxicity. Unfortunately, there is little could be done to limit or prevent adverse effects of drugs on sensory organs. Many of these potentially or overtly toxic drugs are used to prevent or treat life-threatening conditions or have scarce number of analogs that can replace these dangerous compounds. The only possible way to prevent severe complications and adverse effects is constant monitoring of condition of patients treated who take drugs that can cause toxic effects. Patients and doctors should be well-informed of possible side effects and work together to modify treatment plan once slightest signs of toxic impact of a drug arise.
Modifications of treatment usually include rejection of the drug manifesting toxic properties and substitution of it by another drug with relatively similar effect. It is important to perform assessment of sensory organs’ performance before the treatment will begin, periodically during the treatment course and after the treatment is finished. This, along with constant monitoring for toxicity symptoms, could allow the physician to detect early signs of toxic impact and react in due time. Early signs of toxic affection are usually mild, and after drug rejection these signs relatively quickly fade away up to complete recovery. Especially careful should be those patients who belong to the groups of risk of increased toxicity expectation.
They should consider probability of toxic adverse effects much more accurately and consult their physicians more thoroughly. Certain factors contribute to increase of risks. Among these factors are young or senior age, previous experience of damage to sensory organs, genetic susceptibility to drugs or low drugs tolerance, kidney problems, previous experience of taking drugs that are toxic to sensory organs, incorrect dose administration, generally poor health, dehydration of the organism, bacteremia or abnormal biochemical values (Bauman, 2006). Another important notion to prevent sensory toxicity is recommendation to avoid simultaneous administration of several drugs that are toxic to sensory organs, especially to the same sensory organ.
Simultaneous administration increases risk of toxicity dramatically. References: 1. Bacon P. , Spalton D. J. , Smith S. E. (1988). Blindness from quinine toxicity. The British Journal of Ophtalmology, 72(3), 219-24. 2. Bauman, N. (2006). Ototoxicity—The Hidden Menace. Retrieved January 11, 2009, from http://www. hearinglosshelp. com/articles/ototoxicupheaval. htm 3. Berdis A. J. (2008). DNA polymerases as therapeutic targets. Biochemistry, 47(32), 8253-60. 4. Liebler D. C. (2008). Protein damage by reactive electrophiles: targets and consequences. Chemical Research in Toxicology, 21(1), 117-28. 5. Mills J. H. , Going J. A. (1982). Review of environmental factors affecting hearing.
Environmental Health Perspectives, 119-27. 6. Owczarek J. , Jasinska M. , Orszulak-Michalak D. (2005). Drug-induced myopathies. An overview of the possible mechanisms. Pharmacological Reports: PR, 57(1), 23-34. 7. Sanford-Smith, J. H. (1974). Transient myopia after aspirin. British Journal of Ophthalmology, 58, 698. 8. Sainami, G. S. ; Balsara, A. B. (1970). Stevens-Johnson syndrome. Journal of the Indian Medical Association, 54, 512. 9. Spiteri M. A. , James D. G. (1983). Adverse ocular reactions to drugs. Postgraduate Medical Journal, 59(692), 343-9. 10. Wood R. W. (1978). Stimulus properties of inhaled substances. Environmental Health Perspectives, 69-76.