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In support of this conclusion, extensive epidemiological data in epileptic patients suggest that phenobarbital and other anticonvulsants do not function as thyroid (or liver) tumor promoters in humans (Parkinson et al. In some cases, glucuronidation represents an important event in the toxicity of xenobiotics. For example, the aromatic amines that cause bladder cancer (such as benzidine, 2-aminonaphthalene, and 4-aminobiphenyl) undergo N-hydroxylation in the liver followed by N-glucuronidation of the resultant N -hydroxyaromatic amine, although direct N-glucuronidation also occurs, and is a competing pathway of hepatic metabolism. In the case of 4-aminobiphenyl, the competing pathways of ring hydroxylation and O-esterification (i. Benzidine and 2-aminonaphthalene are particularly tumorigenic; with accumulating data which demonstrates that the risk of bladder cancer may increase by up to 100fold in workers exposed to these substances in the course of their occupation in various manufacturing processes (Al-Zoughool et al. The N -glucuronides of such carcinogens, which accumulate in the urine of the bladder, are unstable in acidic pH and thus are hydrolyzed to the corresponding unstable, tumorigenic N hydroxyaromatic amine, as shown in Fig. Concordant with this scenario, benzidine has been shown to induce predominantly liver tumors in rats (fast acetylators) but bladder cancer in dogs (poor acetylators) (Al-Zoughool et al. Male mice, which N -glucuronidate 4aminobiphenyl faster than females, were found during the treatment with this carcinogen to have a 2. The carcinogenicity of aromatic amines is multifactorial, and involves not only hepatic N-glucuronidation but also hepatic oxidation, hepatic and bladder acetylation, and possibly peroxidation of N -hydroxyN -acetyl aromatic amines in the bladder (Al-Zoughool et al. A similar mechanism may be involved in colon tumor formation by aromatic amines, although in this case hydrolysis of the N -glucuronide is probably catalyzed by -glucuronidase in intestinal microflora. Some acylglucuronides are reactive intermediates that bind covalently to protein by mechanisms that may or may not result in cleavage of the glucuronic acid moiety, as shown in Fig. Acyl glucuronides vary widely in their reactivity, from the highly reactive zomepirac and tolmetin acyl glucuronides to the less reactive acyl glucuronides of ibuprofen and salicylic acid (Shipkova et al. A relationship between the reactivity of acyl glucuronides and the substitution near the carboxylic acid has been found. In general, -unsubstituted acetic acid derivatives such as zomepirac, tolmetin, and diclofenac exhibit the highest degree of covalent binding, while mono-substituted acetic acids such as fenoprofen show intermediate levels, and fully substituted -acetic acids such as furosemide, ketoprofen, ibuprofen, and suprofen exhibit lower levels of covalent binding (Bolze et al. However, a direct correlation between the ability of acyl glucuronides to give rise to covalent adducts with proteins such as albumin and their ability to cause drug-related toxicity has not been firmly established, and other mechanisms may come into play. For instance, diclofenac is still a widely used drug in spite of the fact that its acyl glucuronide is very reactive, whereas zomepirac, which is less reactive than these other drugs, was withdrawn from the market in 1983 (Chen et al. Covalent binding of acyl glucuronides appears to be selective, with diclofenac acyl glucuronide forming adducts with dipeptidyl peptidase in rat liver, and with aminopeptidase N and sucrase-isomaltase in rat intestine (Shipkova et al. Binding of acyl glucuronides to protein can involve isomerization reactions that lead to the retention of a rearranged glucuronide moiety (Fig. The rank order of the reactivity of the acyl glucuronides of some carboxylic acid-containing drugs determined by this approach is as follows: tolmetin > zomepirac > diclofenac > ketoprofen > fenoprofen > ibuprofen > furosemide (Wang et al. Some glucuronide conjugates have been found to act as substrates for further biotransformation by oxidation or even by further conjugation. Kumar and colleagues demonstrated that formation of the acyl glucuronide of 4 -hydroxydiclofenac leads to an underestimation of hepatic clearance of diclofenac when it is not accounted for. A case report described the formation of an IgM antibody that bound erythrocytes, but only in the presence of the 4 -hydroxydiclofenac acyl glucuronide in a patient that developed hemolysis during diclofenac treatment (Shipkova et al. A determination of the absolute amount of diclofenac acyl glucuronide formed in vivo relative to the amount of 4 -hydroxydiclofenac formed in vivo would be confounded by the rapid hydrolysis of the glucuronide to the aglycone, and it would therefore be likely that detection of 4 hydroxydiclofenac acyl glucuronide would be attributed to oxidative metabolism occurring prior to conjugation. Sulfonation Many of the xenobiotics and endogenous substrates that undergo Oglucuronidation also undergo sulfonation, as illustrated in Fig. At least five different Golgi-resident N -acetylglucosamine 6-O-sulfotransferases have been identified in humans.

Under toxic stress condition, the imbalance between fibrogenesis and fibrinolysis leads to enhanced fibrogenesis and excess collagen accumulation- fibrosis. Toxic Effect on Myocardial Regeneration the mainstay of cardiac medicine and therapy has centered on the concept that the heart is a terminally differentiated organ and that cardiac myocytes are incapable of proliferating. Thus, cell death would lead to a permanent loss of the total number of cardiac myocytes. However, this view has been challenged recently due to the identification of cardiac progenitor cells (Anversa et al. These cells are characterized and proposed to be responsible for cardiac repair because these cells can make myocytes and vascular structures. These cells possess the fundamental properties of stem cells, therefore, they are also called cardiac stem cells. They are self-renewing, clonogenic, and multipotent, as demonstrated by reconstitution of infarcted heart by intramyocardial injection of cardiac progenitor cells or the local activation of these cells by growth factors. It is important to note that toxicologic studies of the cardiac progenitor cells have not been done and it is important to determine the potential of cardiac stem cells to help recover from toxic insults. One speculation is that when severe damage to cardiac progenitor cells occurs, the potential for recovery from severe cardiac injury would be limited. The removal of scar tissue or fibrosis in the myocardium in the past has been considered impossible. Although there are no studies that have shown scar tissue is removable, there are observations in animal models of hypertensive heart disease that myocardial fibrosis is recoverable (Weber, 2005). Many toxic insults affect the capacity of angiogenesis in the myocardium, so that cardiac ischemia occurs. The combination of cardiac ischemia and the direct toxic insults to cardiomyocytes constitute synergistic damage to the heart. During regeneration, coronary arterioles and capillary structures are formed to bridge the dead tissue (scar tissue) and supply nutrients for the survival of the regenerated cardiomyocytes. There is an orderly organization of myocytes within the myocardium and a well-defined relationship between the myocytes and the capillary network. This proportion is altered under cardiac toxic conditions; either toxicologic hypertrophy or diminished capillary formation can lead to hypoperfusion of myocytes in the myocardium. Unfortunately, our understanding of the toxic effects on myocardial angiogenesis is limited. Cardiomyopathy was viewed not to be recoverable in the past, but there is cumulative evidence that demonstrates reversibility of cardiomyopathy. The issue related to whether or not toxicologic cardiac lesions are reversible has not been explored. However, it can be speculated that there would be reversible and irreversible manifestations of the cardiac response to toxic insults. Myocardial Cell Death and Signaling Pathways Apoptosis and Necrosis Toxic insults trigger a series of reactions in cardiac cells leading to measurable changes. However, severe injuries will lead to cell death in the modes of apoptosis and necrosis. If the cell survives the insults, structural and functional adaptations will take place. The loss of cardiac myocytes is a fundamental part of myocardial injury, which initiates or aggravates cardiomyopathy. An important mode of myocardial cell loss is apoptosis, which has been demonstrated in heart failure patients (Olivetti et al. Myocardial apoptosis has been shown to play an important role in cardiac toxic effects induced by Adriamycin (Kang et al. Exposure of primary cultures of cardiomyocytes to cadmium also induces apoptosis (El-Sherif et al. At first glance, this number seems to be too insignificant to account for myocardial pathogenesis. Myocytes that undergo apoptosis are lost and may not be replaced under toxicologic conditions.

He gave the history of having difficulty in passing urine, poor stream, frequent urge to urinate and post-void dribbling for the last 3 years. Over the past few days he had been experiencing episodes of vertigo for which he was prescribed a medicine that he was taking for 2 days. Adrenaline (Adr) It is secreted by adrenal medulla and may have a transmitter role in the brain. This inhibitor can be used in pheochromocytoma before surgery and in inoperable cases. It requires high concentration of glucocorticoids reaching through the intraadrenal portal circulation for induction of the methylating enzyme. The release is modulated by presynaptic receptors, of which 2 inhibitory control is dominant. It may capture circulating Adr, but is quantitatively minor and not of physiological or pharmacological importance. These metabolites are mostly conjugated with glucuronic acid or sulfate before excretion in urine. In some cases the activated G-protein itself operates K+ or Ca2+ channels, or increases prostaglandin production. The indirectly acting sympathomimetic amines like tyramine, but not isoprenaline, also utilize this pump for entering the neurone. This classification was confirmed later by the discovery of selective and adrenergic antagonists. On the basis of relative organ specificity of selective agonists and antagonists the receptors were further subdivided into 1 and 2 subtypes. In the mid 1970s the receptors were demonstrated to be present prejunctionally as well. To differentiate these release inhibitory prejunctional receptors, a subdivision into 1 and 2 was suggested. However, the present classification into 1 and 2 is based on pharmacological criteria (selectivity of agonists and antagonists) and not on anatomical location. Molecular cloning has further identified 3 subtypes of 1 (1A, 1B, 1D) and 3 subtypes of 2 (2A, 2B, 2C) receptors. Though tissue distribution of subtypes of 1 and 2 receptors has been mapped, there is lot of overlap. Sufficiently subtype selective agonists or antagonists have also not yet been developed to pharmacologically exploit the molecular heterogeneity of subtypes of 1 and 2 receptors. A summary of drugs acting through adrenergic neuronal mechanisms is presented in Table 9. Mixed action sympathomimetics They act directly as well as indirectly-ephedrine, dopamine, mephentermine. Contraction of radial muscles of iris mydriasis (1), decreased aqueous secretion 5. Nictitating membrane-contraction (in animals) have been clearly differentiated into those mediated by or receptors depending on the predominant receptor type present in a given tissue. The actions of a particular sympathomimetic amine depend on its relative activity at different types of adrenergic receptors. Certain anaesthetics (chloroform, halothane) sensitize the heart to arrhythmic action of Adr. Conduction velocity through A-V node, bundle of His, atrial and ventricular fibres is increased; partial A-V block may be overcome. Blood vessels Both vasoconstriction and vasodilatation (2) can occur depending on the drug, its dose and vascular bed. The action is most marked on arterioles and precapillary sphincters; larger arteries and veins are affected at higher doses. The mechanism is-rapid uptake and dissipation of Adr concentration around the receptor is reduced low concentrations are not able to act on receptors but continue to act on 2 receptors. Toxic doses of Adr cause pulmonary edema by shifting blood from systemic to pulmonary circuit. Eye Mydriasis occurs due to contraction of radial muscles of iris (1), but this is minimal after topical application, because Adr penetrates cornea poorly. In intact animals and man peristalsis is reduced and sphincters are constricted, but the effects are brief and of no clinical import.

One of the potentially more important outcomes of the collaborative research effort described above was the identification of thiourea cross-linking structures on erythrocyte spectrin and hemoglobin. Viscose rayon worker studies reporting excess cardiovascular morbidity expand the range to Germany (Drexler et al. Aggazzotti G, Fantuzzi G, Righi E, Predieri G: Environmental and biological monitoring of chloroform in indoor swimming pools. Astrand I: Effect of physical exercise on uptake, distribution and elimination of vapors in man, in Fiserova-Bergerova V (ed. Axelson O, Hane M, Hogstedt C: A case-referent study of neuropsychiatric disorders among workers exposed to solvents. Belpoggi F, Soffritti M, Filippini F, Maltoni C: Results of long-term experimental studies on the carcinogenicity of methyl tert-butyl ether. Boffeta P, Garfinkel L: Alcohol drinking and mortality among men enrolled in an American Cancer Society prospective study. Chrostek L, Jelski W, Szmitkowski M, Puchalski Z: Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans. Colborn T: A case for revisiting the safety of pesticides: A closer look at neurodevelopment. Development of a physiologically based pharmacokinetic model for propylene glycol monomethyl ether and its acetate in rats and humans. Cresteil T: Onset of xenobiotic metabolism in children: Toxicological implications. Engelke M, Tahti H, Vaalavirta L: Perturbation of artificial and biological membranes by organic compounds of aliphatic, alicyclic and aromatic structure. Human Health Evaluation Manual Supplemental Guidance, Dermal Risk Assessment, Interim Guidance. Environmental Protection Agency): Trichloroethylene health risk assessment: Synthesis and characterization. Garetano G, Gochfeld M: Factors affecting tetrachloroethylene concentrations in residences above dry cleaning establishments. Ginsberg G, Hattis D, Russ A, Sonawane B: Pharmacokinetic and pharmacodynamic factors that can affect sensitivity to neurotoxic sequelae in elderly individuals. Green T: Methylene chloride induced mouse liver and lung tumors: An overview of the role of mechanistic studies in human safety assessment. Green T: Pulmonary toxicity and carcinogenicity of trichloroethylene: Species differences and modes of action. Haddad S, Charest-Tardif G, Krishnan, K: Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. Hattis D, Erdreich L, Ballew M: Human variability in susceptibility to toxic chemicals-A preliminary analysis of pharmacokinetic data from normal volunteers. Occupational Exposures in Petroleum Refining: Crude Oil and Major Petroleum Fuels. Functional consequences and possible relationship to disease and alcohol toxicity, in Jansson B, Jornvall H, Rydberg U, et al (eds. Jonsson F, Bois F, Johanson G: Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise. Jonsson F, Johanson G: Physiologically based modeling of the inhalation kinetics of styrene in humans using a Bayesian population approach. Kaneko T, Wang P-Y, Sato A: Enzymes induced by ethanol differently affect the pharmacokinetics of trichloroethylene and 1,1,1-trichloroethane. Presented at the Methanol Vapors and Health Effects Workshop: What we know and what we need to know-Summary Report. Environmental Protection Agency/Health Effects Institute/American Petroleum Institute, A-7, 1989. Kayama F, Yamashita U, Kawamoto T, Kodama Y: Selective depletion of immature thymocytes by oral administration of ethylene glycol monomethyl ether. Kiesswetter E, Sietmann B, Seeber A: Standardization of a questionnaire for neurotoxic symptoms. Kiesswetter E, Sietmann B, Zupanic M, Seeber A: Neurobehavioral study on the interactive effects of age and solvent exposure.