Multiorgan Toxicity Metals

Widely used metal responsible for multi-organ toxicity, some of which may occur over extended periods of time and may depend on the route of exposure. Thus it causes acute testicular damage in rodents and kidney damage after chronic exposure or delayed after acute exposure. May also be hepatotoxic, causes effects on vascular tissue and bone and Leydig cell tumours. Detoxified by being bound to metallothionein and binds to other proteins containing available SH groups. Enzyme inhibition...

Disturbances Of The Central Nervous System

Toxic substances can interfere with normal neurotransmission in a variety of ways, ether directly or indirectly, and cause various central effects. For example, cholinesterase inhibitors such as the organophosphate insecticides cause accumulation of excess acetylcholine. The accumulation of this neurotransmitter in the CNS in humans after exposure to toxic insecticides leads to anxiety, restlessness, insomnia, convulsions, slurred speech and central depression of the respiratory and circulatory...

A initiation b promotion c progression

It is currently a matter of debate exactly how many stages are involved, but the important factor is that it is a multistage process. Experimental studies have revealed certain features of the carcinogenic process 1 The initiator must be given before the promoter. 2 Repeated doses of an initiator may cause tumours in the absence of a promoter. 3 The initiator produces an irreversible change. 4 The initiator is often chemically reactive and interacts with DNA whereas the promoter does not. 5 The...

Absorption

Absorption of foreign compounds from various sites is dependent on the physiological and physical conditions at these sites. These, of course, may be subject to species variations. Absorption of compounds through the skin shows considerable species variation. Table 5.2 gives an example of this and shows the species differences in toxicity of an organophosphorus compound absorbed percutaneously. Human skin is generally less permeable to chemicals than that of rabbits, mice and rats, although...

Access to the embryo and foetus

For foreign compounds, in contrast to ionizing and other radiation or mechanical force, the route of access is via the maternal body. This is either through the fluids surrounding the embryo or via the blood, following the formation of the placenta. The blood from the maternal circulation enters a sinus into which the vessels of the embryo protrude like fingers (figure 6.15). Consequently, there is rapid and efficient exchange between maternal and embryonic blood for most foreign substances,...

Acetylation

Acetylation is an important route of metabolism for aromatic amines, sulphonamides, hydrazines and hydrazides and there is a wide variety of substrates. This metabolic reaction is one of two types of acylation reaction and involves an activated conjugating agent, acetyl CoA. It is hence a type 1 reaction. Acetylation is notable in that the product may be less water soluble than the parent compound. This fact gave rise to problems with sulphonamides when these were administered in high doses....

Actinomycin D

Actinomycin D is a complex chemical compound produced by the Streptomyces species of fungus and is used as a antibiotic. It is a well established and potent teratogen and is also suspected of being carcinogenic. The teratogenic potency of actinomycin D shows a marked dependence on the time of administration, being active on days 7-9 of gestation in the rat, when a high proportion of surviving foetuses show malformations (figure 6.13). Administration of the compound at earlier times, however...

Activation of cellular oncogenes

Cellular oncogenes, termed proto-oncogenes in their normal state, are found in the DNA of cells and are important in the regulation of cell growth. Carcinogenesis is a multistage process involving inappropriate activation of normal cellular genes to become oncogenes (e.g. ras) or inactivation of tumour supressor genes (e.g. p53). Thep53 gene is mutated in the majority of human cancers. The ras oncogene is also important in mouse tumours but the p53 gene is rarely involved in chemically induced...

Age

GILLETTE, J.R. and STRIPP, B. (1975) Pre- and post-natal enzyme capacity for drug metabolite production. Fed. Proc, 34, 172. KINIRONS, M.T. and CROME, P. (1997) Clinical pharmacokinetic considerations in the elderly. KLINGER, W. (1990) Biotransformation of xenobiotics during ontogenetic development. In Frontiers of Biotransformation, Vol. II, Principles, Mechanisms and Biological Consequences of Induction, edited by K.Ruckpaul and H.Rein (London Taylor & Francis). NEIMS, A.H., WARNER, M.,...

Alcohol And Aldehyde Oxidation

Although in vitro a microsomal enzyme system has been demonstrated which oxidizes ethanol (see above), probably the more important enzyme in vivo is alcohol dehydrogenase, which is found in the soluble fraction in various tissues. The coenzyme is normally NAD, and although NADP may be utilized, the rate of the reaction is slower. The enzyme is relatively non-specific and so accepts a wide variety of substrates including exogenous primary and secondary alcohols. Secondary alcohols are...

Aliphatic Hydroxylation

As well as unsaturated aliphatic compounds such as vinyl chloride mentioned above which are metabolized by epoxidation, saturated aliphatic compounds also undergo oxidation. The initial products will be primary and secondary alcohols. For example the solvent -hexane is known to be metabolized to the secondary alcohol hexan-2-ol and then further to hexane-2,5-dione (figure 4.9) in occupationally exposed humans. The latter FIGURE 4.8 Hydroxylation of aniline and nitrobenzene. FIGURE 4.8...

Amine Oxidation

As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate...

Aps Atp 3Phcsph Mdtflt5

> ll0sp l04ljjp l ltt (pa ps j + adp The conjugation is catalysed by a sulphotransferase enzyme which is located in the FIGURE 4.54 Sulphate conjugation of aniline. FIGURE 4.54 Sulphate conjugation of aniline. FIGURE 4.55 Formation of 3-phosphoadenosyl-5-phosphosulphate (PAPS). FIGURE 4.55 Formation of 3-phosphoadenosyl-5-phosphosulphate (PAPS). cytosol and is found particularly in the liver, gastrointestinal mucosa and kidney. There are several different sulphotransferases, classified by...

Apt 2Hup

HA + + H1 -> HO- + Fe1 + K.O Hydroxyl radicals are cytotoxic and can be involved in the production of further active oxygen species such as singlet oxygen. FIGURE 6.10 The various protective roles of reduced glutathione (GSH) and the relationship with oxidized glutathione (GSSG). Fpred and Fpox are the FIGURE 6.10 The various protective roles of reduced glutathione (GSH) and the relationship with oxidized glutathione (GSSG). Fpred and Fpox are the reduced and oxidized forms of a flavoprotein...

Aromatic Hydroxylation

Aromatic hydroxylation such as that depicted in figure 4.3 for the simplest aromatic system, benzene, is an extremely important biotransformation. The major products of aromatic hydroxylation are phenols, but catechols and quinols may also be formed, arising by further metabolism. One of the toxic effects of benzene is to cause aplastic anaemia, which is believed to be due to an intermediate metabolite, possibly hydroquinone. As a result of further metabolism of epoxide intermediates (see...

Basepair Transformations

The smallest unit of mutation is the transformation of a single base pair. There are two mechanisms by which this may occur FIGURE 6.23 Deamination of cytidine to uridine by the action of nitrous acid. FIGURE 6.23 Deamination of cytidine to uridine by the action of nitrous acid. a the chemical modification of a base b the incorporation of a mutagen into the DNA molecule or a mutagen causing erroneous base pairing. If the transformation involves the same type of base, that is a purine or...

BENZO[aPYRENE

The polycyclic aromatic hydrocarbons constitute a large group of compounds, which includes a number of carcinogens found originally in coal tar but which have since been detected in cigarette smoke, the exhaust fumes from internal combustion engines, and smoke from other processes involving the burning of organic material. Benzo a pyrene is one of the most intensely studied, as it is an extremely potent carcinogen. Although chemically stable, in vivo polycyclic aromatic hydrocarbons undergo a...

Bibliography

ALVARES, A.P. and PRATT, W.B. (1990) Pathways of drug metabolism. In Principles of Drug Action, edited by W.B.Pratt and P.Taylor (New York Churchill Livingstone). ARMSTRONG, N.R. (1997) Structure, catalytic mechanism and evolution of the glutathione transferases. Chem. Res. Toxicol., 10, 2. BENEDETTI, M.S. and DOSTERT, P. (1994) Contribution of amine oxidases to the metabolism of xenobiotics. Drug. Metab. Rev., 26, 507. BEEDHAM, C. (1988) Molybdenum hydroxylases. In Metabolism of Xenobiotics,...

Biological factors 531 Species

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of...

Blebbing Of The Plasma Membrane

This process is an early morphological change in cells often seen in isolated cells in vitro but also known to occur in vivo. The blebs, which appear before membrane permeability alters, are initially reversible. However, if the toxic insult is sufficiently severe and the cellular changes become irreversible, the blebs may rupture. If this occurs vital cellular components may be lost and cell death follows. The occurrence of blebs may be due to damage to the cytoskeleton which is attached to...

Blood

As almost all foreign compounds are distributed via the bloodstream, the components of the blood are exposed at least initially to significant concentrations of toxic compounds. Damage to and destruction of the blood cells results in a variety of sequelae such as a reduced ability to carry oxygen to the tissues if red blood cells are destroyed. Aromatic amines such as aniline and the drug dapsone (4,4-diaminodiphenyl sulphone) are metabolized to hydroxylamines, and in the latter case the...

Carcinogenic effects Phenobarbital and 3methylcholanthrene reduce demethylation However inhibition of metabolism by

Toxic and carcinogenic effects of dimethylnitrosamine. These data are consistent with there being other routes of metabolism, some of which may be detoxication pathways, which may explain the protective effects of some microsomal enzyme inducing agents. Dimethylnitrosamine is a potent methylating agent, and the degree of methylation of DNA in vivo in various tissues correlates with the susceptibility of those tissues to tumour induction. Thus, metabolism is also important for the...

Carcinogenicity

The potential mutagenicity of a foreign compound may now be rapidly and easily determined using a variety of short-term tests, one of the best known being the Ames test. This test utilizes histidine-requiring mutant strains of Salmonella bacteria. If a foreign compound causes a mutation, the bacteria may then grow on histidine-free medium and can be readily detected. The test has been adapted to utilize liver homogenate, usually from rats or other experimental animals, so as to identify...

Cells is the loss of growth control which allows uncontrolled proliferation It is clear that a permanent heritable

1 Genotoxic carcinogens Primary, direct acting Polycyclic aromatic hydrocarbons Nitrosamines Hydrazines Inorganic 2 Epigenetic carcinogens Promoters 3 Unclassified Peroxisome proliferators Dimethylsulphate Ethylene imine -Propiolactone Benzo a pyrene Dimethylnitrosamine 1,2-Dimethylhydrazine Cadmium, plutonium Phorbol esters Saccharin, bile acids Asbestos, plastic Oestrogens Purine analogues Catechol occurred in the cell because, on division, the daughter cells possess the same characteristics....

Changes In Ca2 Concentration

Perhaps the most important cellular changes described recently in terms of mechanisms of cell injury and death are those involving changes in the concentration of calcium. It has long been known that calcium is in some way involved in cell death, and that it accumulates in damaged tissue. More recently changes in the intracellular distribution of this ion have been implicated in the mechanisms underlying the cytotoxicity of many different, although not all, toxic compounds in different tissues....

Changes in maternal and placental homeostasis

As well as direct effects on the embryo or foetus, foreign compounds can also be teratogenic by influencing the maternal organism or the placenta. Thus, maternal malnutrition or protein deficiency, or a deficiency in one or more vitamins or minerals may lead to effects on the embryo and foetus. As might be expected maternal malnutrition will tend to cause growth retardation. However, vitamin A and folic acid deficiencies cause malformations and embryolethality as well as growth retardation....

Changes In Membrane Structure And Permeability

Both the plasma membrane and internal membranes associated with organelles may be damaged by toxic compounds. As already discussed, this may be due to lipid peroxidation which alters and destroys membrane lipids. As many enzymes and transport processes are membrane bound this will affect the function of the organelle as well as the structure. Sulphydryl groups in membranes may be targets for mercuric ions in kidney tubular cells and for methyl mercury in the CNS for example. The result is...

Changes In Muscle Contractionrelaxation

This type of response may be caused by several mechanisms. For instance, the muscle relaxation induced by succinylcholine, discussed in more detail in Chapter 7, is due to blockade of neuromuscular transmission. Alternatively, acetylcholine antagonists such as tubocurarine may compete for the receptor site at the skeletal muscle end plate, leading to paralysis of the skeletal muscle. Botulinum toxin binds to nerve terminals and prevents the release of acetylcholine the muscle behaves as if...

Changes In The Cytoskeleton

The cytoskeleton may be specifically damaged by toxic compounds such as phalloidin and the cytochalasins. Thus, phalloidin which is a toxic component of certain poisonous mushrooms, binds to actin filaments and stabilizes them. They are thus unable to depolymerize, and this in some way leads to release of Ca2+ from an intracellular compartment. As the cytoskeleton is associated with the plasma membrane, damage to it may underlie the appearance of cell surface blebs which rapidly occur after...

Changes In Water And Electrolyte Balance

Certain foreign compounds may cause the retention or excretion of water. Some, such as the drug furosemide, are used therapeutically as diuretics. Other compounds causing diuresis are ethanol, caffeine and certain mercury compounds such as mersalyl. Diuresis can be the result of a direct effect on the kidney, as with mercury compounds which inhibit the reabsorption of chloride, whereas other diuretics such as ethanol influence the production of antidiuretic hormone by the pituitary. Changes in...

Chapter

1 The therapeutic index is the ratio between the toxic and effective doses of a drug. It is calculated as TD50 ED50 or alternatively LD50 ED50. The larger the ratio the greater the relative safety of the The margin of safety is a similar parameter except that it is calculated as TD1 ED99. It is a more critical parameter than the therapeutic index. 2 Tolerance is the modification of the biological effect of a chemical as a result of repeated dosing. For example repeated dosing with phenobarbital...

Chemical Carcinogenesis

One of the most widely studied carcinogens and a very potent mutagen. It causes tumours to liver, bladder and kidney. Metabolism is important, hence conjugates, (sulphate and acetyl) of A-hydroxyacetylaminofluorene are more potent carcinogens than the parent compound. These may give rise to nitrenium and carbonium ions. Sulphate conjugation leads to cytotoxicity and tumorigenicity and DNA adducts. Some species (guinea pig) are resistant due to lack of formation of the...

Chemical factors

The importance of the physicochemical characteristics of compounds has already been alluded to in the previous two chapters. Thus lipophilicity is a factor of major importance for the absorption, distribution, metabolism and excretion of foreign compounds. Lipophilic compounds are more readily absorbed, metabolized and distributed, but more poorly excreted, than hydrophilic compounds. The distribution of compounds is profoundly affected by lipophilicity and this may in turn influence the...

Cholestatic damage

There are various types of interference with the biliary system, and this can lead to bile stasis or damage to the bile ducts, ductules or canaliculi. In some cases such as with chlorpromazine, damage to the hepatocytes may ensue. Thus, some foreign compounds such as the antibiotic rifampicin, interfere with bilirubin transport and conjugation giving rise to hyperbilirubinaemia. Other compounds, icterogenin for example, cause bile stasis and bilirubin deposits in the canaliculi. This...

Chromosome Breakage And Deletions

This type of effect, clastogenesis, is similar to the foregoing but on a larger scale. Certain compounds cause the breakage of chromosomes, including many of those able to induce base-pair transformations. Alkylating agents, both monofunctional and difunctional, cause chromosome breakage, the latter type probably by causing cross-linking across the DNA molecule. Inhibition of DNA repair may be another cause of this type of mutation. Chromosome breakage may therefore be linked to other...

Chronic toxicity

Chronic toxicity may be quantitated in a similar manner to acute toxicity, using the TD50 or LD50 concept. Measurement of chronic toxicity in comparison with acute-toxicity measurements may reveal that the compound is accumulating in vivo, and may therefore give a rough approximation of the probable whole-body half-life of the compound. For chronic toxicity, the TD50 or LD50 is measured for a specific period of time, such as 90 days of chronic dosing. The dose-response is plotted as the percent...

Competitive Inhibition

Any two compounds which are metabolized by the same enzyme may competitively inhibit the metabolism of the other. The extent of this will depend on the affinity each compound has for the enzyme. One example where this is important toxicologically is in the treatment of ethylene glycol and methanol poisoning. Both of these compounds are toxic as a result of metabolism by the enzyme alcohol dehydrogenase (see Chapter 7). Consequently one method of treatment is to reduce this by administration of...

Conjugation with amino acids

This is the second type of acylation reaction. However, in this type the xenobiotic itself is activated, and it is therefore a type 2 reaction. Organic acids, either aromatic such as salicylic acid (see Chapter 7), or aliphatic such as 2-methoxyacetic acid, are the usual substrates for this reaction which involves conjugation with an endogenous amino acid. The particular amino acid depends on the species of animal exposed although species within a similar evolutionary group tend to utilize the...

Contents

1.3 Biochemical aspects of toxicology 2 1.6 Bibliography 5 CHAPTER 2 DOSE-RESPONSE RELATIONSHIPS 7 2.2 Criteria of toxicity 7 2.4 Measurement of dose-response relationships 16 2.5 Hazard and risk assessment 20 2.9 Bibliography 22 CHAPTER 3 FACTORS AFFECTING TOXIC RESPONSES DISPOSITION 25 3.2 Sites of absorption 33 3.7 Bibliography 62 CHAPTER 4 FACTORS AFFECTING TOXIC RESPONSES METABOLISM 65 4.2 Types of metabolic change 67 4.5 Control of metabolism 106 4.6 Toxication versus detoxication 107 4.9...

Covalent Binding To Macromolecules

As well as free radicals, other reactive intermediates, usually electrophilic species, may be produced by metabolism. These reactive intermediates can interact with proteins and other macromolecules and bind covalently to them. Studies have shown that there is a correlation between both the amount and site of binding and tissue damage. Therefore it was suggested that covalent binding to critical macromolecules was a possible cause of the cellular injury. While this may be true with regard to...

Cysteine conjugate blyase

Cysteine conjugates resulting from initial glutathione conjugation as described above may undergo further catabolism to give the thiol compound, pyruvate and ammonia (figure 4.62). The enzyme which catalyses this reaction, cysteine conjugate b-lyase (or CS lyase), requires pyridoxal phosphate, is cytosolic and will not accept the acetylated cysteine derivative. The thiol conjugate produced as a result of the action of b-lyase may be further metabolized by methylation and then -oxidation (see...

Damage To The Endoplasmic Reticulum

As the smooth endoplasmic reticulum is the site for the oxidative metabolism of many foreign compounds, it is vulnerable to damage from reactive metabolites such as epoxides and free radicals. Short-lived, reactive intermediates with only a narrow radius of action will obviously damage the immediate vicinity. Thus, with carbon tetrachloride, damage to both smooth and rough endoplasmic reticulum occurs leading to disruption of functions, such as metabolism and protein synthesis, of the whole...

Deficiency of energy supply

The rapidly proliferating and differentiating tissue of the embryo would be expected to require high levels of energy, and therefore interference with its supply, not surprisingly, may be a teratogenic action. A deficiency of glucose due to dietary factors or due to hypoglycaemia, which may be induced by foreign compounds, is teratogenic. Interference in glycolysis, such as that caused by 6-aminonicotinamide, inhibition of the tricarboxylic acid cycle as caused by fluoroacetate (see page 307),...

Delayed Neuropathy

Certain organophosphorus compounds, such as tri-orthocresyl phosphate, cause this toxic effect. The symptoms, which may result from a single dose, may not be apparent for 10-14 days afterwards. The result is degeneration of peripheral nerves in the distal parts of the lower limbs which may spread to the upper limbs. Pathologically it is observed that the nerves undergo 'dying back' with axonal degeneration followed by myelin degeneration. The effect does not seem to be dependent on...

Depletion Of Atp And Other Cofactors

Depletion of ATP is caused by many toxic compounds and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds such as 2,4-dinitrophenol which uncouple the production of ATP from the electron transport chain will cause such an effect, but also inhibition of electron transport or depletion of NADH. Excessive...

Desaturation Of Alkyl Groups

This novel reaction which converts a saturated alkyl compound into a substituted alkene and is catalysed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA 2-n-propyl-4-pentanoic acid) (figure 4.29). The mechanism proposed involves formation of a carbon-centred free radical which may form either a hydroxylated product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450 FIGURE 4.29 Aliphatic desaturation of valproic acid. mediated...

Destruction

A number of foreign compounds will destroy enzymes such as cytochromes P-450. Thus, halogenated alkanes, hydrazines, compounds containing carbon-carbon double and triple bonds may all interact with and destroy cytochrome P-450. In many cases this is suicide inhibition, whereby the substrate is metabolized by the enzyme but the product reacts with and destroys the enzyme. Thus drugs containing the alkene group such as secobarbital, allobarbital, fluoroxene and compounds such as...

Detection of hepatic damage

Simple quantitative tests can be used such as measurement of the liver weight body weight ratio. Overt damage to the liver can be detected by light and electron microscopy of liver sections. However, damage can be detected by other non-invasive means such as the urinary excretion of conjugated bilirubin or the amino acid taurine. Various parameters may be measured in plasma. Thus determination of the enzymes aspartate transaminase (AST) and alanine transaminase (ALT) is the most common means of...

Detection of organ damage

There are various ways of detecting damage to organs, in some cases using specific biochemical tests, in others function tests are utilized. Histopathology is generally used at some stage, however, for all types of damage. Thus, for damage to the nervous system and ear, functional tests and histopathology are utilized. For damage to the eye and skin, gross observation may be useful before microscopy. For damage to the reproductive system, hormonal changes may be detected. For testicular damage...

Diet

The influence of diet on drug metabolism, disposition and toxicity consists of many constituent factors. Food additives and naturally occurring contaminants in food may influence the activities of various enzymes by induction or inhibition. However, these factors are discussed in a later section (page 155). The factors with which this section will be concerned are the nutritional aspects of diet. TABLE 5.17 Effect of reduced protein diet on hepatic microsomal enzyme activity in rats TABLE 5.17...

Diffusion or filtration of small molecules through pores is facilitated Specialized

Transport systems also exist for endogenous compounds and ions. Consequently many foreign compounds achieve the same concentration in foetal as in maternal plasma. However, if metabolism in utero converts the compound into a more polar metabolite, accumulation may occur in the foetus. Despite extensive blood flow (16 cardiac output 0.5 ml min g of tissue) entry of foreign compounds into the brain takes place much less readily than passage into other tissues. Hence the term 'blood-brain...

Digitalis Glycosides

Some of the toxic effects of the digitalis glycosides have been known since digitalis was first described by William Withering in 1785. Overdoses cause vomiting, diarrhoea, visual disturbances, hypotension, slow pulse and ventricular tachycardia, eventually leading to ventricular fibrillation, delirium and convulsions. Toxic effects such as vomiting are not infrequent in the clinical use of the drug, as it has a narrow margin of safety, or a low therapeutic ratio. The dose is therefore critical...

Diphenylhydantoin

As with the digitalis glycosides, the toxic effects of the anticonvulsant drug diphenylhydantoin result from elevated plasma levels of the drug. This can simply be due to inappropriate dosage, but other factors may also be involved in the development of toxicity. The toxic effects observed are nystagmus, ataxia, drowsiness and sometimes more serious effects on the CNS. These toxic effects are clearly dose-related and correlate well with the plasma levels of the unchanged drug. High plasma...

Distribution

The distribution of foreign compounds may vary between species because of differences in a number of factors such as proportion and distribution of body fat, rates of metabolism and excretion and hence elimination and the presence of specific uptake systems in organs. For instance, differences in localization of methylglyoxal-bis-guanyl hydrazone (figure 5.4) in the liver accounts for its greater hepatotoxicity in rats than in mice. The hepatic concentration in mice is only 0.3-0.5 of the dose...

Dna Damage And Poly Adpribosylation

Compounds such as hydrogen peroxide and alkylating agents such as dimethyl sulphate which cause single strand breaks in DNA cause the activation of the enzyme poly(ADP-ribose)polymerase. This enzyme catalyses ADP-ribosylation which is post-translational protein modification, involving the addition of ADP-ribose to amino acids. It is also involved in polymerization reactions and, through modulation of DNA ligase activity, with DNA repair. The result of activation of this enzyme is the cleavage...

Dna Repair

If the DNA molecule has sustained damage from a toxic chemical, it can be repaired by the action of various enzymes. The cell is able to recognize and then repair damaged DNA by excision repair. This may involve enzymatic removal of the damaged region of DNA and synthesis of new DNA using the opposite strand as a template. The new section of DNA is then inserted into the damaged DNA molecule. With guanine methylated on the O6 position a methyltransferase removes the methyl group and the damage...

Dose

Although the concentration in tissues is generally related to the dose of the foreign compound, there are various factors which affect this concentration. Thus, the absorption from the site of exposure, distribution in the tissues, metabolism and excretion all determine the concentration at the target site. However, the concentration of the compound may not be directly proportional to the dose, so the dose-response relationship may not be straightforward or marked thresholds may occur. For...

Doseresponse

It is clear from the preceding discussion that the measurable end-point of toxicity may be a pharmacological, biochemical or a pathological change which shows percentage or proportional change. Alternatively the end-point of toxicity may be an 'all-or-none' or quantal type of effect such as death or loss of consciousness. In either case, however, the dose-response relationship is graded between a dose at which no effect is measurable and one at which the maximal effect is demonstrated. The...

Effects

This group of compounds is used as pesticides and nerve gases. The structure and therefore metabolism and potency varies. However, they all act in a similar manner. There are two toxic effects, cholinesterase inhibition and delayed neuropathy, but all OPs do not necessarily cause both. The cholinesterase inhibition results from the similarity between the organophosphorus compound and acetylcholine. The organophosphorus compound therefore acts as a pseudosubstrate but...

Epigenetic mechanisms

Epigenetic carcinogens cause the appearance of tumours without a genotoxic effect. This includes promotion, immunosuppression, cocarcinogenicity and cytotoxicity. This group probably involves diverse mechanisms. They may act by a exposure of a pre-existing genetic abnormality b impairment of DNA polymerase c gene amplification d alteration of chromosome composition e induction of a stable, altered state of gene expression. Other types of carcinogen include the peroxisome proliferators. These...

Esterase Activity

Hydrolysis reactions can also exhibit genetic influences such as the plasma enzyme, a pseudocholinesterase, which is responsible for the metabolism and inactivation of the drug succinylcholine (figure 7.36). Certain individuals may be defective in the ability to hydrolyse, and therefore inactivate, this drug. Such individuals have a form of the enzyme with a decreased hydrolytic activity, and the half-life of the drug is dramatically increased. Consequently, such individuals may be affected by...

Excretion

Although most mammals have similar kidneys, there are functional differences between species and urine pH, and volume and rate of production may vary considerably (table 5.5). Thus, the rate of urine production in the rat is an order of magnitude greater than the rate in man. Although the pH ranges for the urine of a number of mammals may overlap (table 5.5), a small change TABLE 5.6 Urinary excretion of methylglyoxal-bis-guanylhydrazone in mammalian species TABLE 5.6 Urinary...

Excretion Via The Lungs

The lungs are an important route of excretion for volatile compounds and gaseous and volatile metabolites of foreign compounds. For example about 50-60 of a dose of the aromatic hydrocarbon benzene is eliminated in the expired air. Excretion is by passive diffusion from the blood into the alveolus assisted by the concentration gradient. This is a very efficient, usually rapid, route of excretion for lipid soluble compounds as the capillary and alveolar membranes are thin and in very close...

Exposure

Repeated or chronic exposure is required for immunotoxic reactions as the immune system must first be sensitized as described above. The exposure to the compound need not be continuous and in fact repeated, discontinuous exposure is often more potent. There is no generalized, characteristic exposure time or sequence for immunotoxic reactions. In halothane hepatitis (see Chapter 7) the number of exposures seems to be important, with about four being optimal. With the hydralazine-induced Lupus...

Expression

The mechanisms of induction of the cytochromes P-450 will be considered in terms of the different types of inducer. However, some general principles can be considered first. Induction involves increased synthesis of enzyme protein which may be detected as an increase in total enzyme level as with phenobarbital induction or increase in a particular isoenzyme. Protein synthesis is increased and this usually seems to be necessary as inhibition of protein synthesis results in inhibition of...

Female organism As the greatest number of mitoses take place in the foetus exposure to mutagens should be particularly

This is also the period of greatest teratogenic susceptibility. In testing for mutagenic effects in the female mammalian organism, therefore, continuous exposure of the animal to the mutagen may be important, particularly with mutagens which act at the meiosis which occurs during the short period of the maturation of the ovum. In the male, mutagens which act on replicating DNA or on the process of mitosis do so in the foetus and during the period of reproductive life. Mutagens...

Fluoroacetate

Monofluoroacetic acid (fluoroacetate, figure 7.39) is a compound found naturally in certain South African plants, and which causes severe toxicity in animals eating such plants. The compound has also been used as a rodenticide. The toxicity of fluoroacetate was one of the first to be studied at a basic biochemical level, and Peters coined the term lethal synthesis to describe this biochemical lesion. Fluoroacetate does not cause direct tissue damage and is not intrinsically toxic but requires...

Frameshift Mutations

This type of mutation arises from the addition or deletion of a base to the nucleic acid molecule. This puts the triplet code of the genome out of sequence. Consequently, transcription of the information is erroneous when it is carried out distal to the mutant addition or deletion. In illustration of this, the following code makes sense when read in groups of three After the deletion or insertion of a base, however, the code makes no sense HOW CAN THR ATE AT The transcription of information is...

Frequency distribution have rates of oxidation about onequarter of the highest rates and these individuals are probably

Although the investigation of the mechanism underlying paracetamol hepatotoxicity has been of intrinsic toxicological interest, there has also been a particularly significant benefit that has arisen from this work. This is the development of an antidote which is now successfully used for the treatment of paracetamol overdose. The antidote now most commonly used is -acetylcysteine, although methionine is also used in some cases as it can be given orally. There are various mechanisms by which...

Galactosamine

D-Galactosamine is an amino sugar (figure 7.40a) normally found in vivo only in acetylated form in certain structural polysaccharides. Administration of single doses of this compound to certain species results in a dose-dependent hepatic damage resembling viral hepatitis, with focal necrosis and periportal inflammation. As well as a reversible hepatitis after acute doses, galactosamine may also cause chronic progressive hepatitis, cirrhosis and liver tumours. As all the liver cells are affected...

Gastrointestinal Tract

Many foreign substances are ingested orally, either in the diet, or as drugs and poisonous substances taken either accidentally or intentionally. Most suicidal poisonings involve oral intake of the toxic agent. Consequently, the gastrointestinal tract is a very important site and perhaps the major route of absorption for foreign compounds. The internal environment of the gastrointestinal tract varies throughout its length, particularly with regard to the pH. Substances taken orally first come...

Genetic Factors

Inherited differences in the metabolism and disposition of foreign compounds which may be seen as strain differences in animals, and as racial and interindividual variability in man, are of great importance in toxicology. There are many examples of human subjects showing idiosyncratic reactions to the pharmacological or toxicological actions of drugs. In some cases, the genetic basis of such reactions has been established and these cases underline the need for an understanding and appreciation...

Genetic influences

Observations that species and strain differences exist in the susceptibility to certain teratogens suggest that genetic factors may be involved in teratogenesis. Similarly, it seems clear that in some cases at least a teratogen may increase the frequency of a naturally occurring abnormality. These genetic factors may simply be differences in the maternal metabolism or distribution of the compound which lead to variation in the exposure to the ultimate teratogenic agent. It is also clear from...

Glossary

A-carbon first carbon after functional group. acetylator status phenotype genetically determined difference in the acetylation of certain foreign compounds giving rise to rapid and slow acetylators. acidaemia decrease in blood pH. acidosis the condition where the pH of the tissues falls below acceptable limits. aciduria decrease in urinary pH. acro-osteolysis dissolution of the bone of the distal phalanges of the fingers and toes. acyl group such as acetyl, propionyl, etc. acylation addition of...

Glucuronide formation

This is a major, type 1, conjugation reaction occurring in most species with a wide variety of substrates, including endogenous substances. It involves the transfer of glucuronic acid in an activated form as uridine diphosphate glucuronic acid (UDPGA) to hydroxyl, carboxyl, nitrogen sulphur and occasionally carbon atoms. The UDPGA is formed in the cytosol from glucose-1-phosphate in a two-step reaction (figure 4.48). The first step, addition of the UDP, is catalysed by UDP glucose...

Glutathione conjugation

Glutathione is one of the most important molecules in the cellular defence against toxic compounds. This protective function is due in part to its involvement in conjugation reactions, and a number of toxicological examples of this such as bromobenzene and paracetamol hepatotoxicity are discussed later (see Chapter 7). The other protective functions of glutathione are discussed in Chapter 6. Glutathione is a tripeptide (figure 4.56), composed of glutamic acid, cysteine and glycine...

Glutathione

Probably the most important protective mechanisms involve the tripeptide glutathione (figure 4.56). This compound is found in most cells and in liver cells it occurs at a relatively high concentration, about 5 mM or more. It has a nucleophilic thiol group and it can detoxify substances in one of three ways i conjugation catalysed by a glutathione transferase ii chemical reaction with a reactive metabolite to form a conjugate iii donation of a proton or hydrogen atom to reactive metabolites or...

Heterocyclic Hydroxylation

Nitrogen heterocycles such as pyridine and quinoline (figure 4.13) undergo microsomal hydroxylation at the 3 position. In quinoline, the aromatic ring is also hydroxylated in positions o- and p- to the nitrogen atom. T-Phflrtrticpfln cl lJ tiBnjlpracwi-l FIGURE 4.10 Aliphatic oxidation of n-propylbenzene. FIGURE 4.10 Aliphatic oxidation of n-propylbenzene. 1,2 -dig FIGURE 4.11 Hydroxylation of cyclohexane. FIGURE 4.11 Hydroxylation of cyclohexane. FIGURE 4.12 Hydroxylation of tetralin. FIGURE...

Hydration of epoxides

Epoxides, three-membered oxirane rings containing an oxygen atom, may be metabolized by the enzyme epoxide hydrolase. This enzyme adds water to the epoxide, probably by nucleophilic attack by OH- on one of the carbon atoms of the oxirane ring, which may be regarded as electron deficient, to yield a dihydrodiol which is predominantly trans (figure 4.47) although the degree of stereo FIGURE 4.47 Hydration of benzene-1, 2-oxide by epoxide hydrolase. FIGURE 4.47 Hydration of benzene-1, 2-oxide by...

Hydrolysis of hydrazides

The drug isoniazid (isonicotinic acid hydrazide) is hydrolysed in vivo to the corresponding acid and hydrazine, as shown in figure 4.44. However, in man, in vivo, hydrolysis of the acetylated metabolite acetylisoniazid is quantitatively more important and toxicologically FIGURE 4.45 Hydrolysis of acetylisoniazid. FIGURE 4.45 Hydrolysis of acetylisoniazid. more significant (figure 4.45 and see Chapter 7). This hydrolysis reaction accounts for about 45 of the acetylisoniazid produced. These...

Hydropic Degeneration

This term describes the swelling of a cell due to the intake of water. It is a reversible change but may often precede irreversible changes and cell death. The osmotic balance of the cell is maintained by active processes which control the influx and efflux of ions. The intracellular Na+ and Ca2+ concentrations are maintained at a lower level than that in the extracellular fluid by an active process requiring ATP, whereas K+ is maintained at a higher concentration inside the cell. However, the...

Immunosuppression

Drugs and other foreign compounds can inhibit the functioning of the immune system, an activity which has been used in clinical medicine for the suppression of graft rejection. However, it has become clear that this activity may be considered as a toxic response to certain chemicals as it causes secondary effects such as increased susceptibility to infection. This toxic effect has been observed in both experimental animals and humans after exposure to environmental pollutants and industrial...

Info

Thus step 1 involves addition of NADPH and reduction of the flavin, step 2 the addition of oxygen. At step 3 an internal rearrangement results in the formation of a peroxy complex which then binds the substrate at step 4. The substrate is oxygenated and released at step 5. Step 6 regenerates the enzyme. In the absence of a suitable substrate the complex at step 3 may degrade to produce hydrogen peroxide. This enzyme system catalyses the oxidation of various nitrogen, sulphur and phosphorus...

Inhibition of enzymes

Teratogens in this category are also included in some of the previous categories. Enzymes of central importance in intermediary metabolism are particularly vulnerable, such as dihydrofolate reductase, which may be inhibited by folate antagonists giving rise to a deficiency in folic acid. 6-Aminonicotinamide, which inhibits glucose-6-phosphate dehydrogenase, an important enzyme in the pentosephosphate pathway, is a potent teratogen. 5-Fluorouracil (figure 3.6) an inhibitor of thymidylate...

Interaction of carcinogens with other macromolecules such as RNA and the proteins

FIGURE 6.30 Relationship between the binding of carcinogens to DNA and carcinogenic potency. Adapted from Brookes (1966) Cancer Res., 26, 1994. FIGURE 6.30 Relationship between the binding of carcinogens to DNA and carcinogenic potency. Adapted from Brookes (1966) Cancer Res., 26, 1994. C-Afkvlnuarwic N7-AI kvlfluarrno FIGURE 6.31 O6 and N7 alkylation of guanine. C-Afkvlnuarwic N7-AI kvlfluarrno FIGURE 6.31 O6 and N7 alkylation of guanine. which regulate gene function may also be involved in...

Interaction with DNA

There are numerous cellular targets with which carcinogens may interact, but attention has focused on nucleic acids, particularly DNA. It is indisputable that many carcinogens are electrophiles (direct acting or procarcinogens) which react covalently with DNA as well as other cellular macromolecules. The fact that the neoplastic transformation is heritable implies that an alteration in DNA may have occurred, and the observation that many cancers have altered gene expression and chromosomal...

Introduction

The relationship between the dose of a compound and its toxicity is central in toxicology. Paracelsus (1493-1541), who was the first to put toxicology on a scientific basis, clearly recognized this relationship. His well-known statement 'All substances are poisons there is none that is not a poison. The right dose differentiates a poison and a remedy', has immortalized the concept. Implicit in this statement is the premise that there is a dose of a compound which has no observable effect and...

Involves the first meiotic division occurs in foetal life These primary oocytes do not mature into ova until

FIGURE 6.28 Gametogenesis in humans showing the number of nuclear divisions giving rise to the gametes. Each average fertilizing spermatozoon is the result of900 divisions of the primary spermatogonium. FIGURE 6.28 Gametogenesis in humans showing the number of nuclear divisions giving rise to the gametes. Each average fertilizing spermatozoon is the result of900 divisions of the primary spermatogonium. puberty, with the second meiotic division yielding one ovum from each primary oocyte (figure...

K lHbOJ[QJ K g IHbpiUQj K [HAKO

(The smaller the dissociation constant, the more tightly the oxygen is bound.) When all four oxygen molecules are bound, each is equivalent. Loss of the first oxygen occurs when the partial pressure of the ambient oxygen falls. This loss of oxygen triggers a co-operativity change that facilitates the loss of the second oxygen molecule thus K2> K. Similarly loss of the second oxygen facilitates loss of the third oxygen (K3> K ). Loss of the fourth oxygen does not normally occur. Loss of the...

Kidney

The function of the kidney is to filter waste products and toxins out of the blood while conserving essential substances such as glucose, amino acids and ions such as sodium. Anatomically the kidney is a complex arrangement of vascular endothelial cells and tubular epithelial cells, the blood vessels and tubules being intertwined. The functional unit of the kidney is the nephron (figure 6.8). Although all nephrons have their glomeruli and primary FIGURE 6.8 Schematic representation of a...

Lack Of Cofactors

Clearly, where cofactors are involved in a metabolic pathway, a lack of these will result in a decrease in metabolic activity. Thus depletion of hepatic glutathione by compounds such as diethyl maleate or inhibition of its synthesis by compounds such as buthionine sulphoximine will decrease the ability of the animal to conjugate foreign compounds with glutathione. Salicylamide and borneol will deplete animals of UDP-glucuronic acid by forming glucuronide conjugates. Galactosamine (figure 7.40)...

Liningcell damage

Direct damage to cells of the respiratory tract, either by airborne compounds or those in the blood, may cause necrosis and changes in permeability leading to oedema. This may be due to the action of the parent compound such as nitrogen dioxide or ozone or to a metabolite as is the case with ipomeanol (see Chapter 7). The former two compounds cause peroxidation of cellular membranes (see below), and phosgene destroys the permeability of the alveolar cell membrane following hydrolysis to carbon...

Lipid Solubility

Passive diffusion relies on dissolution of the compound in the lipid component of the FIGURE 3.4 Role of blood flow and ionization in the absorption offoreign compounds. Both blood flow and ionization create a gradient across the FIGURE 3.4 Role of blood flow and ionization in the absorption offoreign compounds. Both blood flow and ionization create a gradient across the membrane. From Timbrell, J.A., Introduction to Toxicology. Taylor and Francis, London, 1989. membrane and therefore only...

Lung

The lung is a particularly vulnerable organ as regards toxic substances since it can be exposed to foreign compounds both in the external environment, and also internally from the bloodstream. The lungs receive 100 of the cardiac output and therefore are extensively exposed to substances in the blood. Also, the air breathed in may contain many potentially toxic substances irritant gases such as sulphur dioxide, particles of dust, of metals and of other substances such as asbestos, solvents and...

Lungs

Exposure to and absorption of toxic compounds via the lungs is toxicologically important and more significant than skin absorption. The ambient air in the environment whether it is industrial, urban or household, may contain many foreign substances such as toxic gases, solvent vapours and particles. The lungs have a large surface area, around 50-100 m2 in humans they have an excellent blood supply and the barrier between the air in the alveolus and the blood stream may be as little as two cell...

Malemediated Teratogenesis

This is a controversial area with regard to humans where there is currently little hard data. Theoretically it is possible for a foreign compound to cause mutations in male germ cells which result in malformations or the development of abnormal offspring. This is similar to the situation in which inherited mutations or chromosomal aberrations lead to the birth of abnormal offspring, such as occur in Down's syndrome, for example, where an extra chromosome occurs (Trisomy 21). Although this has...

Manifestations of abnormal development

The final consequences of abnormal development are death, malformation, growth retardation FIGURE 6.15 The structure and blood supply of the mammalian placenta. Adapted from Gray, H., Anatomy of the Human Body, edited by C.D.Clemente (Philadelphia Lea & Febiger), 30th Edition. 1985. FIGURE 6.15 The structure and blood supply of the mammalian placenta. Adapted from Gray, H., Anatomy of the Human Body, edited by C.D.Clemente (Philadelphia Lea & Febiger), 30th Edition. 1985. and functional...

Mechanism And Response In Cellular Injury

Toxic compounds can damage cells in target organs in a variety of ways and the cellular injury caused, by such compounds leads to a complex sequence of events. The eventual response may be reversible injury or an irreversible change leading to the death of the cell. The processes leading to cell death and the 'point of no return' for a cell are not yet clearly understood and are the subject of considerable research, speculation and some controversy. However, some of the key elements are known,...

Mechanisms Of Teratogenesis

Because the process of development of the embryo and then the foetus is a complex series of events it is clear that many different mechanisms may cause the disruption that underlies the teratogenic effects of foreign compounds. In many cases the initiating events probably occur at the subcellular or molecular level in the embryo, but may be only detectable as malformations or cell death. FIGURE 6.17 The dose-response patterns for teratogenicity caused by the cytotoxic agent...

Methylation

Amino, hydroxyl and thiol groups in foreign compounds may undergo methylation in vivo (figure 4.66) in the same manner as a number of endogenous compounds. The methyl donor is S-adenosyl methionine formed from methionine and ATP (see Chapter 7, figure 7.41) and so again it is a type 1 reaction with an activated donor. The reactions are catalysed by various methyltransferase enzymes which are mainly cytosolic although some are located in the endoplasmic reticulum. Some of these enzymes are...