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For example generic pregabalin 150 mg free shipping, polycyclic aromatic hydrocarbons generic pregabalin 150 mg overnight delivery, phenols buy generic pregabalin 75mg on-line, and hydroquinones are oxidized to electrophilic quinones order pregabalin 75mg without a prescription. Acetaminophen is similarly converted to a quinoneimine, namely, N -acetyl-benzoquinoneimine, a cytotoxic electrophile that binds to cellular proteins, as shown in. The formation of this toxic metabolite by cytochrome P450 causes centrilobular necrosis of the liver. Activation of aflatoxin B1 by cytochrome P450, leading to liver tumor formation, and by peroxidases, leading to renal papilla neoplasia. Conjugation with sulfonate, glucuronic acid, or glutathione represents detoxication reactions. Many of the aromatic amines known or suspected of causing bladder cancer in humans have been shown to cause bladder tumors in dogs. In rats, however, aromatic amines cause liver tumors by a process that involves N-hydroxylation by cytochrome P450, followed by conjugation with acetate or sulfonate, as shown in. It was previously mentioned in this section that phenol can enhance the peroxidative metabolism of hydroquinone, which is an important component to benzene myelotoxicity. For example, the peroxyl radical of phenylbutazone can convert benzo[a]pyrene 7,8-dihydrodiol to the corresponding 9,10-epoxide. Note that the peroxyl radical can oxidize xenobiotics (X) in a peroxidative manner. Hydrogen peroxide is a normal product of cellular respiration, and lipid peroxides can form during lipid peroxidation. The level of these peroxides and their availability for peroxidase reactions depends on the efficiency of hydroperoxide scavenging by glutathione peroxidase and catalase. Zwitterions, positively-multiple charged compounds, and diamines such as cadaverine are generally not substrates (Krueger et al. This final step is important because it is rate limiting, and it occurs after substrate oxygenation. Consequently, this step determines the upper limit of the rate of substrate oxidation. Such xenobiotics include various thiols, thioamides, 2-mercaptoimidazoles, thiocarbamates, and thiocarbamides. These electrophilic metabolites, like the sulfenic acid metabolite produced from spironolactone thiol (see above), bind to critical nucleophiles (such as proteins) or interact with glutathione to form disulfides. These reactions involve S-oxygenation adjacent to a ketone, which produces strong electrophilic acylating agents, which may be responsible for the toxicity of many thiocarbamate herbicides and fungicides. In vivo, the S,S-dioxide is more likely to form, which readily tautomerizes to iminosulfinic acid, binds covalently to protein (which leads to hepatocellular necrosis) or rearranges to benzamide, a reaction known as oxidative group transfer. About 26% of African Americans, 7% of Puerto Ricans, and 2% of Mexicans have one normal allele and express a functional protein. In contrast, 26% of African Americans, 7% of Puerto Ricans, and 2% of Mexicans have one normal allele and express a functional protein (Cashman and Zhang, 2006). This likely explains why pyrrolizidine alkaloids are highly toxic to rats but not to guinea pigs. The unusual absorbance maximum of cytochrome P450 is due to an unusual fifth ligand to the heme (a cysteine-thiolate). When this thiolate bond is disrupted, cytochrome P450 is converted to a catalytically inactive form called cytochrome P420. The observation that treatment of rats with certain chemicals, such as 3-methylcholanthrene, causes a shift in the peak absorbance of cytochrome P450 (from 450 nm to 448 nm) provided some of the earliest evidence for the existence of multiple forms of cytochrome P450 in liver microsomes. The conversion of cytochrome P450 to cytochrome P420 by detergents and phospholipases helped to establish the hemoprotein nature of cytochrome P450. There are some notable exceptions to the general rule that cytochrome P450 requires a second enzyme. In both cases, cytochrome P450 functions as an isomerase and catalyzes a rearrangement of the oxygen atoms introduced into arachidonic acid by cyclooxygenase (see.
Histologically buy discount pregabalin 150mg on-line, lysosomal alterations are noted initially purchase 150 mg pregabalin with mastercard, followed by damage to the brush border cheap pregabalin 150 mg line, endoplasmic reticulum generic pregabalin 75mg fast delivery, mitochondria, and cytoplasm, ultimately leading to tubular cell necrosis. Interestingly, proliferation of renal proximal tubule cells can be observed early after the onset of nephrotoxicity. Aminoglycosides are highly polar cations; they are almost exclusively filtered by the glomerulus and excreted unchanged. Filtered aminoglycosides undergo proximal tubular reabsorption by binding to anionic phospholipids in the brush border, followed by endocytosis and sequestration in lysosomes of the S1 and S2 segments of proximal tubules. Basolateral membrane binding and uptake also may occur, but this is a minor contribution to the total proximal tubular uptake of aminoglycosides. The earliest lesion observed following clinically relevant doses of aminoglycosides is an increase in the size and number of lysosomes. These lysosomes contain myeloid bodies, which are electron-dense lamellar structures containing undergraded phospholipids. The renal phospholipidosis produced by the aminoglycosides is thought to occur through their inhibition of lysosomal hydrolases, such as sphingomyelinase and phospholipases. Whereas phospholipidosis plays an important role in aminoglycoside nephrotoxicity, the steps between the phospholipid accumulation in the lysosomes and tubular cell death are less clear. One hypothesis suggests that the lysosomes become progressively distended until they rupture, releasing lysosomal enzymes and high concentrations of aminoglycosides into the cytoplasm. The released lysosomal contents can interact with various membranes and organelles and trigger cell death. Aminoglycosides the aminoglycoside antibiotics are so named because they consist of two or more amino sugars joined in a glycosidic linkage to a central hexose nucleus. Whereas they are drugs of choice for many gram-negative infections, their use is primarily limited by their nephrotoxicity. The incidence of renal dysfunction following aminoglycoside administration ranges from 5 to 25%, but seldom leads to a fatal outcome (Servais et al. Amphotericin B Amphotericin B is a very effective antifungal agent whose clinical utility is limited by its nephrotoxicity (Bernardo and Branch, 1997; Palmer and Heinrich, 2004). Renal dysfunction associated with amphotericin B treatment is dependent on cumulative dose and is due to both hemodynamic and tubular effects. Amphotericin B nephrotoxicity is unusual in that it impairs the functional integrity of the glomerulus and of the proximal and distal portions of the nephron. Some of the renal tubular cell effects of amphotericin B are due to the ability of this polyene to bind to cholesterol in the plasma membrane and form aqueous pores. In the presence of amphotericin B, cells of the turtle and rat distal tubule do not produce a normal net outward flux of protons due to an increase in proton permeability (Steinmetz and Husted, 1982; Gil and Malnic, 1989). The hypokalemia observed with amphotericin B may be due to an increase in luminal potassium ion permeability in the late distal tubule and the cortical collecting duct and the loss of potassium ions in the urine. Renal handling of aminoglycosides: (1) glomerular filtration, (2) binding to the brush-border membranes of the proximal tubule, (3) pinocytosis, and (4) storage in the lysosomes. Cyclosporine is a fungal cyclic polypeptide and acts by selectively inhibiting T-cell activation. Nephrotoxicity is a critical side effect of cyclosporine, with nearly all patients who receive the drug exhibiting some form of nephrotoxicity. Clinically, cyclosporine-induced nephrotoxicity may manifest as (1) acute reversible renal dysfunction, (2) acute vasculopathy, and (3) chronic nephropathy with interstitial fibrosis (Mason and Moore, 1997; Dieperink et al. Endothelin may contribute to constriction of the afferent arteriole because endothelin receptor antagonists inhibit cyclosporine-induced vasoconstriction (Lanese and Conger, 1993). Whereas cyclosporine can produce proximal tubular epithelial changes (many small equally sized vacuoles in the cytosol), it is still not clear whether a direct effect of cyclosporine on tubular cells plays a significant role in the nephrotoxicity. Acute vasculopathy or thrombotic microangiopathy is a rather unusual nephrotoxic lesion that affects arterioles and glomerular capillaries, without an inflammatory component, following cyclosporine treatment. The lesion consists of fibrin-platelet thrombi and fragmented red blood cells occluding the vessels (Charney et al. Whereas the characteristics of this lesion differ from the vascular changes of acute rejection, a variety of factors may contribute to this lesion in the clinical transplant setting.
Furthermore buy pregabalin 75mg with amex, HgCl2 produced similar changes in various respiratory parameters when added to isolated rat renal cortical mitochondria (Weinberg et al discount 75 mg pregabalin fast delivery. The enzymes within this family have different biochemical characteristics cheap pregabalin 150 mg with mastercard, substrate preferences generic pregabalin 150 mg on-line, and Ca2+ dependencies. Lysophospholipids can be toxic to cells and alter membrane permeability characteristics and uncouple mitochondrial respiration. Furthermore, the eicosanoid products of arachidonic metabolism are chemotactic for neutrophils, which may also contribute to tissue injury. Caspases are another class of cysteine proteinases that play a role in the initiation and execution of renal cell apoptosis. The administration of a pan-caspase inhibitor blocked the increase in caspase activities and renal injury following ischemia/reperfusion injury (Daemen et al. Using renal cell models, many studies have demonstrated that nephrotoxicants induce apoptosis that is sensitive to caspase inhibitors. However, it should be noted that caspase activity is not required for apoptosis to occur (Cummings et al. Signaling Kinases Signaling kinases such as protein kinase C, mitogen activated protein kinases. Numerous recent studies reveal critical roles for signaling kinases in renal cell death and in the recovery of renal cells after toxicant injury (Table 14-4) (Schnellmann and Cummings, 2006). Endonucleases Endonucleases have been suggested to play a role in renal cell oncosis and apoptosis. Proteinases Calpains are likely candidates for a role in cell death because they are cysteine proteinases; they are activated by calcium; and they have cytoskeletal proteins, membrane proteins, and enzymes as substrates. For example, calpain activity increased in rat proximal tubules subjected to hypoxia, and calpain inhibitors were cytoprotective (Edelstein et al. Calpain inhibitors with different mechanisms of action decreased cell death produced by a variety of toxicants, suggesting that calpains may play an important role in the cell death produced by a diverse range of toxicants (Waters et al. Recent data reveal that mitochondria have a resident calpain, calpain 10, and that mitochondrial Ca2+ accumulation results in mitochondrial calpain 10 activation which causes mitochondrial dysfunction (Arrington et al. It is important to recognize that the nature and severity of metal nephrotoxicity varies with respect to its form. For example, salts of inorganic mercury produce a greater degree of renal injury and a lesser degree of neurotoxicity than do organic mercury compounds, an effect that has been associated with the greater degree of lipophilicity of organic mercury compounds (Conner and Fowler, 1993; Zalups and Lash, 1994). For example, potassium dichromate and cadmium primarily affect the S1 and S2 segments of the proximal tubule, whereas mercuric chloride affects the S2 and S3 segments (Zalups and Lash, 1994; Zalups and Diamond, 2005). Thus, metals may cause renal cellular injury through their ability to bind to sulfhydryl groups of critical proteins within the cells and thereby inhibit their normal function. Mercury Humans and animals are exposed to elemental mercury vapor, inorganic mercurous and mercuric salts, and organic mercuric compounds through the environment. Administered elemental mercury is rapidly oxidized in erythrocytes or tissues to inorganic mercury, and thus the tissue distribution of elemental and inorganic mercury is similar. Due to its high affinity for sulfhydryl groups, virtually all of the Hg2+ found in blood is bound to cells- albumin, other sulfhydryl-containing proteins, glutathione, and cysteine. The kidneys are the primary target organs for accumulation of Hg2+, and the S3 segment of the proximal tubule is the initial site of toxicity. As the dose or duration of treatment increases, the S1 and S2 segments may be affected. Renal uptake of Hg2+ is very rapid with as much as 50% of a nontoxic dose of Hg2+ found in the kidneys within a few hours of exposure. Considering the fact that virtually all of the Hg2+ found in blood is bound to an endogenous ligand, it is likely that the luminal and/or basolateral transport of Hg2+ into the proximal tubular epithelial cell is through cotransport of Hg2+ with an endogenous ligand such as glutathione, cysteine, or albumin, or through some plasma membrane Hg2+ -ligand complex (Zalups and Diamond, 2005). Current evidence indicates that at least two mechanisms are involved in the proximal tubular uptake of Hg2+. One mechanism appears to involve the apical activity of -glutamyl transpeptidase, cysteinylglycinase, and the transport of Cys-S-Hg-S-Cys through one of more amino acid transporters.
A number of studies have described the pathogen- 100 80 60 40 20 0 1 2 3 ** * * ** ** 0 mg/kg/d 5 mg/kg/d 10 mg/kg/d * ** ** ** 4 5 6 7 8 16 Weeks post-dosing Figure 20-22 pregabalin 150 mg without a prescription. Effect of m-dinitrobenzene on percentage of females pregnant in a serial mating study design pregabalin 150 mg mastercard. Note range of germ cell types affected consequent to the Sertoli cell injury produced by the compound cheap 150 mg pregabalin with mastercard. And the reversibility of the effects after 16 weeks (two spermatogenic waves see pregabalin 150 mg without prescription. The earliest features of these studies after a single dose (250 or 500 mg/kg/d) were that there are Sertoli cell vacuoles and swollen germ cell mitochondria, followed by (or concurrent with) a breakdown of the membrane between the Sertoli cell and the pachytene spermatocyte in a spermatogenic stage-specific manner. This is followed quickly (within hours) by the death of (probably those) pachytene spermatocytes (Creasy et al. Effect of Ethylene glycol monomethyl ether (or its metabolite mehtoxyacetic acid) 24 hours after a single oral dose (100 mg/kg/d). Note the damaged spermatocytes (arrows) in lower tubule compared to the upper normal tubule. As with other testis toxicants, higher dose levels produce a more widespread lesion involving other cell types (Foster et al. The Sertoli cell vacuolization regresses after about 12 hours and is not a prominent feature of this lesion as it is with other agents like hexanedione, or some of the phthalate esters. Some weak evidence of involvement of this cell type also comes from some in vitro data with isolated seminiferous tubules. The lesion is not characteristic of a low-androgen testicular lesion, and reduced accessory sex organ weights are not a prominent feature associated with the early testicular pathology. Male and female rat mating behavior is sufficiently stereotyped that it can be easily quantified to assess the effects of toxicants on these behaviors (Gray and Ostby 1998; Gray et al. During mating, the female rat displays proceptive behaviors like ear wiggling and darting to induce the male to mount, and when mounted the female is "receptive" displaying a lordosis posture characterized by a raised head and tail and fully arched back. In experienced male rats, the latency to the first mount is usually on a few seconds, but inexperienced males may take much longer. When the male rat mounts the lordosing female he will display a single pelvic thrust which may or may not result in intromission of the penis into the vagina. Within a few seconds, the male mounts again and this series continues until the male ejaculates. At the beginning of the second series, the male dislodges the copulatory plug, formed from the seminal secretions. The copulatory plug normally fits close to the cervix and it is necessary to facilitate sperm entry into the uterus. It is not unusual to find seven to eight copulatory plugs in the breeding cage the day after mating (Gray et al. If mating does not occur, then the brief rise in serum progesterone declines by the next day. Cervix the mucosa of the uterine cervix does not undergo cyclic desquamation, but there are regular changes in the cervical mucus. Estrogen, which makes the mucus thinner and more alkaline, promotes the survival and transport of sperm. The mucus is thinnest at the time of ovulation and dries in an arborizing, fernlike pattern on a slide. After ovulation and during pregnancy, it becomes thick and fails to form the fern pattern. Disruptions of the cervix may be expressed as disorders of differentiation (including neoplasia), disturbed secretion, and incompetence. The period of receptivity begins at the onset of the dark phase of their light cycle, terminating later in the evening before the next stage of the cycle, defined as estrus which is typically characterized by the display of a vaginal lavage of mostly cornified epithelial cells. This is normally the only time during which the female is receptive to the male and the display of this behavior can be induced in ovariectomized female rats by a sequence of injections of estradiol for a couple of days prior to mating followed by progesterone administration a few hours before the mating trial is Vagina Estrogen produces a growth and proliferation of vaginal epithelium. The layers of cells become cornified and can be readily identified in vaginal smears. Progesterone stimulation produces a thick mucus and the epithelium proliferates, becoming infiltrated with leukocytes. Analysis of vaginal fluid or cytologic studies of desquamated vaginal cells (quantitative cytochemistry) normally reflects ovarian function.
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