Chapter

1 (a) Glucose-6-phosphate dehydrogenase (G6P dehydrogenase) deficiency is a sex-linked genetic disorder. Males who have this disorder are deficient in the enzyme G6P dehydrogenase which is the first enzyme in the pentose phosphate shunt. Lack of this enzyme results in a deficiency in NADPH and therefore an inability to reduce oxidized glutathione (GSSG) to reduced glutathione (GSH) in the red cell. Therefore these individuals suffer when exposed to drugs and other chemicals which can oxidize...

Other Routes

Foreign compounds may be excreted into other body fluids such as sweat, tears, semen or saliva by passive diffusion, depending on the lipophilicity of the compound. Although these routes are generally of minor importance quantitatively, they may have a toxicological significance such as the production of dermatitis by compounds secreted into the sweat for example. The disposition of toxic compounds in biological systems can be divided into four interrelated phases absorption, distribution,...

Carbon Monoxide

Metabolic Activation Carbon Tet

Despite the fact that carbon monoxide is no longer present in the gas used for domestic cooking and heating, it is still a major cause of poisoning. Indeed, it is one of the most important single agents involved in accidental and intentional poisoning resulting in the deaths of several hundred people in Britain each year. There are in fact many sources of carbon monoxide improperly burnt fuel in domestic fires, car exhausts, coal gas, furnace gas, cigarette smoke and burning plastic. Thus...

Of which are detectable in plasma IgA IgD IgE IgG IgM All of the immunoglobulins have certain common structural

FIGURE 6.20 Formation of an antigenic drug-protein conjugate and subsequent stimulation of antibody production. The antibody so produced combines with the conjugate and inactivates it, in some cases by causing precipitation of the complex. FIGURE 6.20 Formation of an antigenic drug-protein conjugate and subsequent stimulation of antibody production. The antibody so produced combines with the conjugate and inactivates it, in some cases by causing precipitation of the complex. of variable and...

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...

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,...

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...

Alcohol Metabolism

Another oxidation reaction which shows variation in human populations is the oxidation of ethanol. This has been shown to be significantly lower in Canadian Indians compared with Caucasians, and thus the Indians are more susceptible to the effects of alcoholic drinks. The rate of metabolism in vivo in Indians is 0.101 g kg h compared with 0.145 g kg h in Caucasians. This seems to be due to variants in alcohol dehydrogenase, although differences in aldehyde dehydrogenase may also be involved....

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...

Anoxia

Lack of oxygen in the tissues may be due to respiratory or circulatory failure or absence of oxygen. Thus, the first situation may arise if a toxic compound affects breathing rate via central control, such as the drug dextropropoxyphene when taken in overdoses, or by effecting respiratory muscles such as Botulinum toxin. The second situation arises when a toxic compound inhibits oxygen transport. The classic example of this is carbon monoxide which binds to haemoglobin in place of oxygen (see...

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...

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...

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 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...

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...

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...

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...

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...

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...

Cytotoxicity

Direct damage to cells leading to cell death and necrosis is one suggested cause of teratogenesis. Thus, cytotoxic compounds such as the alkylating agent A-methyl-A-nitro-A-nitroso-guanidine (MNNG) are teratogenic. This compound causes a spectrum of malformations, embryolethality and growth retardation (figure 6.17). Thus, cell death and reduced proliferation specifically in the target tissue, which may be a limb bud or tissue destined to be an organ, will give rise to a malformation in that...

Dealkylation

Aromatic methyl and ethyl ethers may be metabolized to give the phenol and corresponding aldehyde (figure 4.16), as illustrated by the de-ethylation of phenacetin (figure 5.20). Ethers with longer alkyl chains are less readily O-dealkylated, the preferred route being -1-hydroxylation. The oxidation of nitrogen in tertiary amines, amides, imines, hydrazines and heterocyclic rings may be catalysed by microsomal enzymes or by other enzymes (see below). Thus the oxidation of trimethylamine to...

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...

Desulphuration

Replacement of sulphur by oxygen is known to occur in a number of cases, and the oxy FIGURE 4.25 Oxidative desulphuration of parathion. FIGURE 4.25 Oxidative desulphuration of parathion. genation of the insecticide parathion to give the more toxic paraoxon is a good example of this (figure 4.25). This reaction is also important for other phosphorothionate insecticides. The toxicity depends upon inhibition of cholinesterases and the oxidized product is much more potent in this respect. The...

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

Diphenylhydantoin is an anticonvulsant drug in common use which is suspected of being teratogenic in humans. There is at present insufficient data available to specify the exact type of malformation caused in humans, but in a few cases craniofacial anomalies, growth retardation and mental deficiency have been documented. Heart defects and cleft palate have also been described in some cases in humans. In experimental animals, however, diphenylhydantoin is clearly teratogenic and this has been...

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...

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...

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

Conjugation Naphthalene Images

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...

Heart

The heart is occasionally a target for toxic compounds. Thus, allyllamine specifically damages heart tissue. This is partly due to metabolism of this compound by amine oxidases present in cardiac tissue. The product is allyl aldehyde (acrolein), which is highly reactive and toxic (figure 4.31) as already mentioned in the context of the hepatotoxicity of allyl alcohol. Some compounds such as hydralazine (figure 7.54) may cause myocardial necrosis as a result of their pharmacological action....

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

FIGURE 5.31 A mechanism for the receptor mediated induction of cytochrome P-450 by a polycyclic hydrocarbon such as TCDD. The inducer-receptor complex, a, undergoes a transformation to yield a complex, b, which binds to the DNA. FIGURE 5.31 A mechanism for the receptor mediated induction of cytochrome P-450 by a polycyclic hydrocarbon such as TCDD. The inducer-receptor complex, a, undergoes a transformation to yield a complex, b, which binds to the DNA. yet been isolated for phenobarbital,...

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

There are many ways in which an organism may respond to a toxic compound, and the type of response depends upon numerous factors. Although many of the toxic effects of foreign compounds have a biochemical basis, the expression of the effects may be very different. Thus, the development of tumours may be one result of an attack on nucleic acids, another might be the birth of an abnormal offspring. The interaction of a toxic compound with normal metabolic processes may cause a physiological...

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...

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)...

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...

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...

Methylcholanthrene induction increased binding in the liver and potentiated liver necrosis but again decreased lung

Diethyl maleate treatment, which depletes glutathione, markedly increased covalent binding to protein and decreased the LD50. Analogues of 4-ipomeanol in which the furan ring was replaced by a methyl or phenyl group were very much less toxic and did not covalently bind to lung or liver protein to any great extent. There is good correlation between the toxicity as measured by lethality or LD50, oedemagenesis and covalent binding of radiolabeled ipomeanol to protein (figure 7.25). The reason for...

Microsomal Flavincontaining Monooxygenases

As well as the cytochromes P-450 monooxygenase system there is also a system which involves FAD. This enzyme system is found particularly in the microsomal fraction of the liver and the monomer has a molecular weight of around 65 000. Each monomer has one molecule of FAD associated with it. The enzyme may accept electrons from either NADPH or NADH although the former is the preferred cofactor. It also requires molecular oxygen and the overall reaction is as written for cytochromes P-450 NADPH +...

Mutagenesis In Mammals

The effects of mutagens on mammalian cells in vivo are less clearly defined than their effects on bacterial cells. When mutagens act on mammalian germ cells, inherited defects may arise, and when somatic cells are exposed to mutagens, cellular organization may be disrupted, giving rise to tumours. It now seems clear that many mutagens are carcinogens and most, but not all, carcinogens are mutagenic (see below). Major mutagenic changes in somatic cells will clearly lead to total disruption of...

Necessarily relate to the chemical structure or site of action so dissimilar chemicals can give rise to similar

Action depending on the type of immunological reaction. This type of immunotoxicity usually requires several exposures and there may not be a clear dose-response because the magnitude of the response may depend on immunological factors rather than the concentration of the chemical. The types of immunological response which occur can be categorized as one of four types, three humoral and one cell mediated. Genetic toxicity. A mutation is a heritable change produced in a cell genotype. This can...

Neutrophil phagocytic granulocyte white blood cell nitroso the group NO

Nitroxide the group fN-jO nitrenium the group -N+-H. nm nanometres. nomogram graph such as blood concentration of a compound vs time used for the estimation of the toxicity expected from the compound as in overdose cases. non-vascularized lacking in blood vessels. nucleoside base-sugar (e.g. adenosine). nucleotide base-sugar phosphate (e.g. adenosine triphosphate). ontogenesis development of an organism. oocyte an egg cell may be primary (diploid) or secondary (haploid). opacification becoming...

Nhydroxylation

A-Hydroxylation of primary arylamines, arylamides and hydrazines is also catalysed by a microsomal mixed-function oxidase involving cytochromes P-450 and requiring NADPH and molecular oxygen. Thus, the A-hydroxylation of aniline is as shown in figure 4.21. The A-hydroxylated product, phenylhydroxylamine, is thought to be responsible for the production of methaemoglobinaemia after aniline administration to experimental animals. This may occur by further oxidation of phenylhydroxylamine to...

Olfactory epithelium

This tissue is known to contain a high level of cytochromes P-450 activity. Clearly it is similar to the lung in exposure. An example is the industrial chemical trifluoromethylpyridine which specifically damages the olfactory epithelium in animals exposed to it in the inspired air. The compound is metabolized by V-oxidation and the V-oxide product (or a nitroxide radical) is believed to be responsible for the toxicity (figure 4.20). The activity for this metabolic pathway is particularly high...

Organic Mercury

Mercury in this form, such as methyl mercury, is extremely toxic, mainly affecting the CNS. However, some organomercury compounds such as phenyl and methoxyethyl mercury cause similar toxic effects to inorganic mercury. There have been a number of instances in which human exposure to methyl mercury has occurred, and consequently data is available on the toxic effects to man as well as experimental animals. Methyl mercury was responsible for the poisoning which occurred in Japan, known as...

Oxidative Dehalogenation

Halogen atoms may be removed from xenobiotics in an oxidative reaction catalysed by cytochromes P-450. For example, the anaesthetic halothane is metabolized to trifluoroacetic acid via several steps, which involves the insertion of an oxygen atom and the loss of chlorine and bromine (figure 4.28). This is the major metabolic pathway in man and is believed to be involved in the hepatotoxicity of the drug. Trifluoroacetyl chloride is thought to be the reactive intermediate (see Chapter 7). FIGURE...

Oxidative Stress

When active oxygen species are produced this may lead to a cycle of oxidation and reduction (redox cycle) with electrons being donated to oxygen to yield superoxide. This is the case with paraquat and also a number of cytotoxic quinones. Thus, there is a cyclic process which produces superoxide by adding electrons from paraquat (see Chapter 7) or a semiquinone to oxygen (figure 6.10). The superoxide produced may then be metabolized to hydrogen peroxide by superoxide dismutase, which is further...

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Alkylating agent, from dimethylnitrosamine 265 Allergic reaction 190, 325-7 Allobarbital 168 Allopurinol 167 Allosteric change, with haemoglobin and carbon monoxide 313 metabolism and toxicity 193 Allylisopropylacetamide 77, 168 ALT see Alanine transaminase Amaranth 90 Ames test 243 Amidases 93 Amine oxidases 85-6 Amine oxidation 85-6 Amino acids, conjugation 104, 129 p-Aminobenzoic acid 103, 136-8, 232 Aminobiphenyl 142 2-Aminofluorene 139 Aminoglutethimide 136 Aminoglycosides 187, 288-90...

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Cadmium 192, 201, 245, 334-5 Caffeine 136, 158 Calcium 202-5, 272, 277, 308 ATPases 204 and cell death 204-5 endonucleases 205 oxalate 332 phospholipases 205 proteases 205 Calmodulin 204 Calpains 205 Canaliculi 27, 179 Captopril, binding to plasma proteins 43 Carbamates, hydrolysis of 94 Carbaryl 94, 165, 166 Carbon disulphide 83, 192, 193 Carbon monoxide 13, 70, 169, 311-14 Carbon tetrachloride 91, 168, 181, 203-5, 206, 269-72 age effect 148 destruction of P-450 270 lipid peroxidation 271-2...

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Cocarcinogenicity 245 Codeine, demethylation 159 Colchicine 216, 223, 240 Compartments 49-50 Complement system 231 hydralazine and 330 Conjugated dienes 272 Conjugation reactions 95-106 Contraceptive steroids 184 Co-operativity 312 Copy choice 239 Coumarin 80, 125 Covalent binding to macromolecules 199-200 paracetamol and 274-6 Creatine kinase 195 Creatinine 188 Crigler-Najjar syndrome 135, 151 Crossover mutation 239 Crystalluria 331, 332 C-S lyase 286 Cyanide 202, 314-16 Cyanomethaemoglobin...

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-1,2-Dichlorovinylthiol 287 Diet, as a factor in toxicity 144-5, 266 Diethylhexylphthalate 156, 192 1,2-Diethylhydrazine 191 Diethylmaleate 100-1, 169 Diethylstilboestrol 19, 77, 88s 153, 193, 226 Diffusion, passive 56 Digitalis glycosides 214, 301-2 Digitoxin 212, 301-2 Diglutathionyl conjugate of bromobenzene 281 Digoxin 19 Dihydrodiol 94, 262-3 Di-isopropylfluorophosphate 19, 300 Dimercaprol 4-5, 338 Dimethoate 126 iraws-4-Dimethylaminostilbene 152 Dimethylformamide 80, 81...

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K region 262 Esterases 92, 143 Estragole 154 Ethanol 4, 85, 86, 97, 135, 143, 153, 159-60, 163, 207 as an antidote 332, 334 Etheno-DNA adducts -deoxyadenine 269 -deoxycytidine 269 Ethinyloestradiol 168 Ethionine 181, 206, 246, 309-11 Ethnic distribution of acetylator phenotype 139 Ethyl morphine 144, 158, 168 Ethylene glycol, toxicity 124, 167, 330-2 Ethylene imine 245 Excision repair 241 Excretion 55-60 Eye, as a target organ 194 affecting detoxication 108 affecting disposition 113-69...

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Hydrazoic acid 213 Hydrogen peroxide 204 Hydrogen sulphide 105 Hydrolysis 92-4 species differences in 125-6 strain differences in 130-1 Hydroperoxide 71 Hydroperoxy radical 198 Hydropic degeneration 208 N-Hydroxyacetanilide 96 N-Hydroxyacetylaminofluorene 96, 97 Hydroxyalkenals 198, 204 6- -Hydroxycortisol 164 6-Hydroxydopamine 152, 196, 295 Hydroxyl radicals 198-9, 293 Hydroxylation 74-82 of nitrogen 82, 259 Hydroxylator status 139-43 4-Hydroxynonenal 198, 204, 271 Hydroxyproline, and bone...

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Damage to, cadmium and 334-5 detection of 188 lead and 339, 340 mercury and 336-7 as target organ 185-8 Kinins 231 isozyme C4 and testicular toxicity 195 Lactic acidosis, and ethylene glycol 331-2 Lactoperoxidase 88 Lauric acid, and ffl-1-hydroxylation 72 LC50 17 blood-brain barrier and 146 and bone 339 and calcium 204 and haem synthesis 339 lung absorption 37 methylation and 105 toxicity 338-41 uptake 32, 41 Lethal synthesis 307-11 Lewisite 4 Lidocaine, binding to plasma protein 146 Lipid...