Biologic Markers in Urinary Toxicology (1995) / Chapter Skim
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3 BIOLOGIC MARKERS OF SUSCEPTIBILITY AND EXPOSURE
3 BIOLOGIC MARKERS OF SUSCEPTIBILITY AND EXPOSURE
Pages 53-80
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From page 53... ...
The power of biologic markers of exposure can be increased if they are linked to biologic mariners of susceptibility and effect. Malting that linkage provides a means to identify a real high-risk group among those exposed and can also provide an understanding of the mechanisms of disease.
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From page 54... ...
In any case, there seems to be a sex-related effect in both rats and humans; whether these differences are genetic in origin remains to be determinecl. Direct evidence of race as a risk factor in toxicant-induced renal injury is lacking, but blacks and some other minority groups are highly susceptible to other forms of renal disease, such as has been demonstrates!
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From page 55... ...
Susceptibility to develop Gooclpasture's syndrome, with anti-gIomerularbasement-membrane antibodies, appears to be strongly associated with a very small number of Class II major histocompatibility antigens; other Class II histocompatibility antigens have been implicated in susceptibility to membranous nephropathy (Oliveira, 1992~. The link with immune response genes is of special importance in susceptibility to toxic injury, inasmuch as organic solvents, heavy metals, and drugs have also been suggested to play a role in the pathogenesis of those immune disorders of glomeruli (see Chapter 4~.
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From page 56... ...
Nutrition The gIomerular hyperfiltration that regularly follows the ingestion of a protein-rich diet can induce glomerulosclerosis and chronic renal failure in animals deprived of their renal reserve. Furthermore, variation in the body's mineral content has been linI`ect with chronic renal injury, as in the case of 56 severe hypoicalemia induced by eating disorders, and shown to augment toxicant-caused injury, as in the association of calcium depletion with leac!
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From page 57... ...
Patients with sicide-cell disease who have a high incidence of renal papilIary necrosis as a result of their underlying disease process also have a predisposition to analgesic use because of the pain associated with "sicide crisis." In this situation, it is difficult to determine whether the analgesic use increases the severity of the papillary necrosis. Another example of the relationship between pre-existing renal insufficiency and acute nephrotoxic renal failure is the increased risk of nephropathy associated with contrast medium in patients with diabetes mellitus or multiple myeloma.
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From page 58... ...
Occupational or Environmental Exposure Drugs and environmental toxicants have in some instances induced acute renal failure but evidence of their causing the development or progression of chronic renal failure is circumstantial and thus less compelling. That is not surprising, given the insidious and progressive nature of chronic renal failure and the long latency between exposure and the onset of disease.
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From page 59... ...
For example, in two separate population studies of the relationship of exposure to aromatic amines and the development of blamer cancer, outcome could not be predicted on the basis of the industrial-hygiene guidelines for estimates of peak exposure, but outcome and duration of exposure were statistically correlated. Epidemiologic studies are useful for identifying xenobiotic substances with overt health effects and to set standards for exposure, but it might be difficult to determine the percentage of people who suffer adverse health effects of low-level exposure or of exposures to multiple agents in population studies.
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From page 60... ...
The mechanism by which this increase occurs ap pears to be an increase in GSH synthesis in renal proximal tubules (Lash and Zalups, 1994~. Nutritional status can be an important determinant of responsiveness to toxicants.
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From page 61... ...
An example of how species (differences contribute to differences in interorgan patterns of metabolism is the processing of GSH and GSH S-conjugates, which undergo a series of metabolic transformations involving enzymes of the liver, biliary epithelium, small intestinal epithelium, and renal proximal tubular epithelium (Lash et al., 1988~.
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From page 62... ...
Each cell population possesses a distinct complement of drug-metabolism pathways, so the bioactivation mechanism for a specific chemical might differ among regions of the nephron. For example, one mechanism might occur in proximal tubular cells and another in the medulIary thick ascending limb 62 celIs.
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From page 63... ...
Prostaglandin H synthase (PHS) is a hemecontaining protein found predominantly in the interstitial and collecting duct cells of the renal medulla and in smaller amounts in HenIe's loop and medulIary thick ascending limb, and it is associated with the endoplasmic reticulum and nuclear membranes.
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From page 64... ...
Al u to thion e -De pen d en t Activation of Nephrotoxicants The traditional view of the mercapturic acid pathway is that GSH forms conjugates with reactive electrophiles, the conjugates are processed to highly polar mercapturates, and these are readily excretes! in the urine (Chasseaud, 1979~.
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From page 65... ...
or reabsorbed into renal proximal tubular cells by active, sodium-dependent transport across the brush-border membrane (Schaeffer and Stevens, 1987~. Because only 30% of plasma is fiIterecl through the glomeruli during a single pass through the renal circulation, a substantial portion of chemicals cleared by the kidneys is tal |
From page 66... ...
GSH Conjugation of Halogenated Alkanes and Alkenes by Cytosolic and Microsomal GSH S-Tra7~sferases Enzymatic conjugation of nephrotoxic halogenated alkalies and allcenes with GSH is the initial step in the bioactivation process. Hepatic GSH Stransferases are found as a family of isoenzyrnes in cytoso!
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From page 67... ...
A complete understanding of the bioactivation pathway is therefore essential for assessing human risk of injury and for developing useful markers of exposure.
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From page 68... ...
That indicates that factors besides a bioactivating enzyme are necessary to determine the tissue and cell-type specificity of cysteine Sconjugate toxicity because nontarget 68 tissues can also produce reactive metabolites from cysteine S-conjugates. Renal cysteine conjugate beta-lyase activity is PLP-dependent and is fount!
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From page 69... ...
The metabolism of nephrotoxic and nephrocarcinogenic cysteine S-conju gates to thioacylating intermediates is consistent with DNA and protein alIcylation and inhibition of thioldependent enzymatic activities as mechanisms of toxicity (Banici and Anders, 1989; Chen et al., 1990a; Lock and Schnellmann, 1990; Vamvalcas et al., 1989b,c)
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From page 70... ...
As the {kinetics and regulation of those interacting pathways become better understood, they will increase the ability to define susceptibility. Moreover, many of the terminal metabolites or products of reactive metabolites and cellular macromolecules can be developed into early mariners of exposure.
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From page 71... ...
Conventional karyotyping and interphase karyotyping with fluorescence in situ hybridization (FISH) are being used to identify common chromosomal abnormalities, which might identify chromosomes that contain tumor-suppressor genes or oncogenes.
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From page 72... ...
For example, acetylation inactivates aromatic amines, which are important carcinogens. Consequently, slow acetylators exposed to those compounds have a higher incidence of bladder cancer than do fast acetylators.
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From page 73... ...
As with all mariners of exposure, interpretation in terms of inclividual risk requires linkage to susceptibility and specific effects. Acquired Conditions Predisposing to Bladder Cancer Some congenital and acquired clinical conditions influence susceptibility to bladder cancer.
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From page 74... ...
In summary, the balance between differentiating cells fated for apoptotic cleath and initiated cells, the differential effects of xenobiotic exposure on foci of initiated cells and on normal cells, and any differential proliferative responses among stem and differentiating cells or among initiated cells can lead to carcinogenesis. Cancer of the Prostate Few data support a prominent role for occupational or environmental toxicants in the genesis of prostatic carcinoma, but the sharp differences in prevalence of prostatic cancers around the 74 world and the convergence toward a prevalence in migrated ethnic groups similar to that in indigenous populations suggest prominent environmental factors.
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From page 75... ...
an earlier age of onset of malignancies of multiple organ sites. Other cancers, including multiple myeloma and head and neck tumors, have been associated with prostatic cancer; this suggests the potency of the underlying carcinogenic process.
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From page 76... ...
76 TABLE 3-5 Cancers of the Urinary Tract Associated with Environmental Agents Renal parenchyma Renal adenoma and adenocarcinoma Aromatic amines Nitroso compounds Hydrazines Allcylating agents Anticancer drugs Cadmium and lead Squamous-cell carcinoma Various chemical carcinogens Chronic infections Renal Pelvis or Ureter Transitional-cell carcinoma Papillary tumors Various industrial carcinogens Urothelial carcinoma Ball~an nephropathy Analgesics Transitional-cell carcinoma Cigarette-smoking Coffee-drinl~ing Aromatic amines (2 naphthylamine, xenylamine) Squamous-cell cancer Chronic irritation, such as presence of urinary calculi Chronic urinary tract infection Neurogenic bladder Parasitic infection Adenocarcinoma Bladder extrophy Persistent urachus The criterion of stability refers to the chemical properties of the mariner or metabolize; markers of exposure are generally terminal metabolites that are chemically unreactive (or not very reac
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From page 77... ...
spectrometry techniques has expanded the ability to detect stable, terminal metabolites noninvasively, but NMR techniques are generally not very sensitive. HPLC analysis of urinary metabolites obtained after exposure of rats to the hepatotoxic and nephrotoxic halogenated hydrocarbon trichioroethylene showed only the oxidation products generated by cytochrome P-450 (Dekant et al., 1986a)
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From page 78... ...
A different approach to the use of biologic markers for nephrotoxicant exposure was developed by Woods and colleagues (Bowers et al., 1992~. They determined that urinary porphyrin excretion patterns are altered in response to methyl mercury exposure and that the changes can correlate with both the magnitude of exposure ant!
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From page 79... ...
The possible link between a family history of renal disease and the development of renal failure might be an inherited susceptibility or a common geographic exposure. Altered nutrition and some coexisting diseases, including addictive behavior, are additional characteristics that indicate increased risk associated with nephrotoxicants.
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