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The liver expresses a number of uptake transporters that actively remove xenobiotics from the blood anxiety hypnosis purchase desyrel mastercard. They also express a number of efflux transporters that actively discharge xenobiotics or their metabolites (especially conjugates) into the bile canaliculus for biliary excretion anxiety meds generic desyrel 100 mg free shipping, or that actively discharge xenobiotic metabolites (especially conjugates) across the sinusoidal membrane back into the blood for urinary excretion anxiety 24 hour helpline purchase desyrel 100mg free shipping. The liver expresses the largest number and anxiety symptoms headaches 100 mg desyrel for sale, with few exceptions, the highest concentrations of xenobiotic-biotransforming enzymes. Although the liver contains higher concentrations of most xenobiotic-biotransforming enzymes, and because the number of hepatocytes in the liver exceeds the number of enterocytes in the small intestine, it might be assumed that, compared with the liver, the small intestine would make only a small contribution to first-pass metabolism, but this is not the case. The small intestine and liver are exposed to high concentrations of xenobiotics, and they possess high levels of the enzymes that potentially convert xenobiotics to reactive or toxic metabolites. It is perhaps not surprising, therefore, that both tissues possess protective mechanisms to minimize the risk of xenobiotic toxicity and carcinogenicity. As already mentioned, both tissues have enzymes and transporters that facilitate the elimination of xenobiotics and their metabolites. In both tissues, several of the xenobioticbiotransforming enzymes and transporters are inducible, enabling the liver and the small intestine to respond to high levels of xenobiotics by enhancing the rate of xenobiotic biotransformation and elimination. In the small intestine, the enterocytes at the villus tips undergo extensive turnover, such that the mature cells that are exposed to high levels of xenobiotics and/or reactive metabolites are quickly lost (exfoliated) and replaced in a matter of days. In addition, severely damaged hepatocytes can undergo apoptosis (cell-programmed death) to eliminate precancerous cells. Point 16 Some of the same mechanisms that protect the small intestine and liver from xenobiotic toxicity also protect certain organs such as the brain and reproductive organs. Efflux transporters and glutathione transferases are often over-expressed in tumor cells as a result of chromosomal rearrangements that place the genes encoding these proteins under the control of a strong promoter. Point 17 In view of the important role of cytochrome P450 in the metabolic activation of proximate carcinogens to ultimate carcinogens, it may seem paradoxical to list cytochrome P450 induction among the defense mechanisms that protect organisms from the carcinogenic effects of xenobiotics. Activation by cytochrome P450 is definitely required for certain xenobiotics to exert their carcinogenic effects, and induction of cytochrome P450 is associated with an increase in the toxicity of certain xenobiotics. However, contrary to expectation, treatment of rodents with a cytochrome P450 inducer prior to treatment with a known proximate carcinogen (such as aflatoxin, various nitrosamines, or polycyclic aromatic hydrocarbons) is generally associated with a decrease, not an increase, in tumor incidence (Parkinson and Hurwitz, 1991). Nevertheless, enzyme induction appears, for the most part, to provide protection against chemical carcinogenesis. Point 18 Although the small intestine and liver contain the highest concentrations, xenobiotic-biotransforming enzymes are nevertheless widely distributed throughout the body. Xenobiotic-biotransforming enzymes in the lung, eye, and skin can be especially important for the metabolism of drugs delivered by inhalation, eye drop, or topical application, respectively. The kidney expresses several xenobioticbiotransforming enzymes, in addition to numerous transporters that actively secrete xenobiotics (especially acidic metabolites) into urine. Point 19 Species differences in xenobiotic-biotransforming enzymes are often the basis for species differences in both the qualitative and quantitative aspects of xenobiotic biotransformation and toxicity. As mentioned in Point 14, species difference in coumarin metabolism and toxicity (activation by epoxidation in rats, detoxication by aromatic hydroxylation in humans) reflects a species difference in hepatic microsomal cytochrome P450, whereas species differences in glutathione transferase activity account for the difference between rats and mice in terms of their susceptibility to aflatoxin-induced liver toxicity. Biotransformation, inhibition, and induction can occur in a species-specific manner. Such species differences are the impetus for the development of so-called humanized mice, which involves substituting the murine genes that encode xenobiotic-metabolizing enzymes (and the receptors that regulate their expression) with their human counterparts (Gonzalez, 2003; Gonzalez and Yu, 2006). For example, cats and dogs are considered poor glucuronidators and poor acetylators of xenobiotics, respectively. Point 20 In sexually mature rats and, to a lesser extent, mice there are marked gender differences in the expression of certain xenobiotic-biotransforming enzymes (both oxidative and conjugating enzymes). In other species, including humans, gender differences either do not exist or they generally represent less than a twofold difference, whereas the differences in rodents can be an order of magnitude or greater.
However anxiety triggers order desyrel 100 mg free shipping, there is no evidence for a relevant role of apoptotic cell death in animals or patients for both drugs (Gujral et al anxiety symptoms 4 dpo purchase desyrel us. Thus anxiety symptoms zinc buy desyrel discount, characterization of cell death after chemical exposure has to be primarily based on morphology and a number of additional biochemical parameters anxiety symptoms fear effective desyrel 100mg, which need to quantitatively correlate with the number of apoptotic cells. In addition, the relevance of the model system for the human pathophysiology needs to be considered. The mechanisms of oncotic necrosis are more diverse and depend on the chemical insult to the cell (a detailed example of the mechanism of acetaminophen-induced hepatocellular necrosis is discussed later). Independent of the initial insult and signaling pathways, mitochondria are almost always involved in the pathophysiology. Canalicular Cholestasis this form of liver dysfunction is defined physiologically as a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile. Cholestasis is characterized biochemically by elevated serum levels of compounds normally concentrated in bile, particularly bile salts and bilirubin. When biliary excretion of the yellowish bilirubin pigment is impaired, this pigment accumulates in skin and eyes, producing jaundice, and spills into urine, which becomes bright yellow or dark brown. Because drug-induced jaundice reflects a more generalized liver dysfunction, it is considered a more serious warning sign in clinical trials than mild elevations of liver enzymes (Zimmerman, 1999). The histologic features of cholestasis can be very subtle and difficult to detect without ultrastructural studies. Structural changes include dilation of the bile canaliculus and the presence of bile plugs in bile ducts and canaliculi. Toxicant-induced cholestasis can be transient or chronic; when substantial, it is associated with cell swelling, cell death, and inflammation. Many different types of chemicals, including metals, hormones, and drugs, cause cholestasis (Table 13-2) (Zimmerman, 1999). The molecular mechanisms of cholestasis are related to expression and function of transporter systems in the basolateral and canalicular membranes (reviewed by Pauli-Magnus and Meier, 2006). In principle, an increased hepatic uptake, decreased biliary excretion, and increased biliary reabsorption (cholehepatic shunting) of a drug may contribute to its accumulation in the liver. A substantial inhibition of bile salt excretion can lead to accumulation of these compounds in hepatocytes and may directly cause cell injury (Palmeira and Rolo, 2004). In addition, the initial tissue injury can be aggravated by the subsequent inflammatory response (Gujral et al. However, the increased bile acid levels can trigger compensatory mechanisms, which limit the injury potential of cholestasis (Zollner et al. Thus, the pharmacological modulation of transporter expression may counteract some of the detrimental effects of cholestasis with various etiologies (Zollner et al. Bile Duct Damage Another name for damage to the intrahepatic bile ducts is cholangiodestructive cholestasis (Cullen and Ruebner, 1991; Zimmerman, 1999). A useful biochemical index of bile duct damage is a sharp elevation in serum activities of enzymes localized to bile ducts, particularly alkaline phosphatase. In addition, serum levels of bile acids and bilirubin are elevated, as observed with canalicular cholestasis. Initial lesions following a single dose of cholangiodestructive chemicals include swollen biliary epithelium, debris of damaged cells within ductal lumens, and inflammatory cell infiltration of portal tracts. However, only in rare cases will there be permanent damage or even loss of bile ducts, a condition known as vanishing bile duct syndrome. Cases of this persisting problem have been reported in patients receiving antibiotics (Davies et al. Sinusoidal Damage the sinusoid is, in effect, a specialized capillary with numerous fenestrae for high permeability (Braet and Wisse, 2002). The functional integrity of the sinusoid can be compromised by dilation or blockade of its lumen or by progressive destruction of its endothelial cell wall. The rare condition of primary dilation, known as peliosis hepatis, has been associated with exposure to anabolic steroids and the drug danazol. Blockade will occur when the fenestrae enlarge to such an extent that red blood cells become caught in them or pass through with entrapment in the interstitial space of Disse. Endothelial cell gaps and injury have been shown after exposure to acetaminophen (Ito et al.
Although the embryo has compensatory mechanisms to offset such effects anxiety symptoms at bedtime buy generic desyrel from india, production of a normal or malformed offspring will depend on the balance between damage and repair at each step in the pathogenetic pathway anxiety lightheadedness cheap desyrel 100mg mastercard. Mirkes anxiety attacks symptoms purchase 100mg desyrel otc, 1992) anxiety vs stress buy 100mg desyrel visa, which constitutes a relatively greater proportion of the cell cycle in the heart than in the neuroepithelium. The p53 gene, which may function as a tumor suppressor, can promote apoptosis or growth arrest. Apoptosis occurring during normal development does not require this gene, as p53-deficient embryos develop normally. However, p53 may be critical for induction of growth arrest or apoptosis in re- Advances in the Molecular Basis of Dysmorphogenesis Our still limited understanding of normal development, combined with the small size and inaccessibility of the mammalian embryo, have made the elucidation of mechanisms of abnormal development a daunting task. However, advances in molecular biology, genomics, and proteomics are bringing new understanding of mechanisms of normal and abnormal development. Chambon and colleagues have produced mice lacking several of these receptors either singly or as multiple knockouts. By 24 hour postdosing, cell cycle distributions have returned to normal at 20 mg/kg, but remain abnormal at higher dosages. The use of synthetic antisense oligonucleotides allows temporal and spatial restriction of gene ablation. Added advantages of the antisense approach are the ability to ablate multiple gene family members (by making the antisense probes to regions of sequence homology) and the much shorter time frame for the experiments (Sadler and Hunter, 1994). The proto-oncogenes Wnt-1 and Wnt-3a have been implicated in the development of the midbrain and hindbrain. Exposure during neurulation produced mid- and hindbrain malformations similar to those seen in Wnt-1 null mutant mice, as well as cardiac anomalies not observed in Wnt-1 knockouts created by homologous recombination. Antisense attenuation of Wnt-3a caused anomalies of the forebrain, midbrain, and spinal cord. Simultaneously attenuating both Wnt-1 and Wnt-3a targeted all brain regions and worsened the effect on the spinal cord, suggesting that these genes may serve a complementary function in the development of the central nervous system. Gain of gene function can also be studied by engineering genetic constructs with an inducible promoter attached to the gene of interest. Ectopic gene expression can be made ubiquitous or sitespecific depending on the choice of promoter to drive expression. Ectopic expression of the Hoxa-7 gene induced in mouse embryos by attaching it to the chicken -actin promoter resulted in a phenotype exhibiting multiple craniofacial and cervical vertebral malformations (Balling et al. Transient overexpression of specific genes can be accomplished by adding extra copies using adenoviral transduction. In proof-of-concept, Hartig and Hunter (1998) injected the adenoviral vector containing either the bacterial beta-galactosidase or green fluorescent protein reporter gene under the control of the human cytomegalovirus early gene promoter into the intraamniotic space of neurulation-stage mouse embryos and achieved intense gene expression in the neuroepithelium. Advances in gene targeting and transgenic strategies now allow modification of gene expression at specific points in development and in specific cell types. Conditional knockouts or knock-ins, inducible gene expression and other techniques are being used to study the effects of specific gene products on development in great detail (Mikkola and Orkin, 2005). Reporter transgenes contain a gene with a readily detectable product fused downstream of a selected regulatory region. The Escherichia coli lacZ (-galactosidase) gene is commonly used for this purpose. The reporter gene will then be expressed in and mark all progeny of the transfected cell. This method has been used to study postimplantation development in the mouse embryo (Sanes et al. The pattern of expression of a particular gene of interest can be discriminated by fusing upstream regulatory elements of the gene to lacZ, which will then be transcribed under control of those upstream elements (Zakany et al. Regions of altered hox expression could be manifest as abnormal cell fate and morphogenesis (Marshall, 1996; Collins and Mao, 1999). The maternal, placental, and embryonic compartments are distinct yet interacting systems that undergo profound changes during the course of pregnancy. Changes in maternal physiology during pregnancy involve hepatic metabolism, the gastrointestinal tract, cardiovascular system, excretory system, and the respiratory system (Hytten, 1984; Krauer, 1987; Mattison et al.
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Tight binding of phalloidin to actin filaments prevents the disassembly phase of the normally dynamic rearrangement of the actin filament constituent of the cytoskeleton anxiety symptoms muscle twitches order desyrel 100 mg with amex. Phalloidin uptake into hepatocytes leads to striking alterations in the actin-rich web of cytoskeleton adjacent to the canalicular membrane; the actin web becomes accentuated and the canalicular lumen dilates (Phillips et al anxiety symptoms journal desyrel 100 mg free shipping. Experiments using time-lapse video microscopy have documented dose-dependent declines in the contraction of canalicular lumens between isolated hepatocyte couplets after incubation with a range of phalloidin concentrations (Watanabe and Phillips anxiety breathing techniques purchase desyrel cheap online, 1986) anxiety symptoms for days buy cheap desyrel. Reversible phosphorylations of cytoskeletal structural and motor proteins are critical to the dynamic integrity of the cytoskeleton. Extensive hyperphosphorylation produced by large amounts of microcystin leads to marked deformation of hepatocytes due to a unique collapse of the microtubular actin scaffold into a spiny central aggregate (Hooser et al. Lower doses of microcystin, insufficient to produce the gross structural deformations, diminish uptake and secretory functions of hepatocytes in association with preferential hyperphosphorylation of the cytoplasmic motor protein dynein (Runnegar et al. Chronic exposure to low levels of microcystin has raised new concerns about the health effects of this water contaminant. Specifically, low levels of microcystin promote liver tumors and kill hepatocytes in the zone 3 region, where microcystin accumulates (Solter et al. Information about the binding of phalloidin and microcystin to specific target molecules is valuable for two reasons. First, the linkages of specific binding to loss of target protein functions provide compelling evidence that such binding constitutes a defined molecular mechanism of injury. Second, the demonstrations of high-affinity binding to a target molecule without confounding effects on other 566 processes or tissues have translated into applications of these toxins as tools for cell biology research. The collapse of actin filaments into spiny aggregates after microcystin treatment was visualized by fluorescence microscopy of cells stained with rhodamine phalloidin (Hooser et al. Low levels of microcystin are being used to discriminate the roles of dynein from other cytoskeletal motor proteins (Runnegar et al. This effect does not only lead to steatosis but also to increased reactive oxygen formation and lipid peroxidation. Fatty Liver Fatty liver (steatosis) is defined biochemically as an appreciable increase in the hepatic lipid (mainly triglyceride) content, which is <5% by weight in normal human liver. Histologically, in standard paraffin-embedded and solvent-extracted sections, hepatocytes containing excess fat appear to have multiple round, empty vacuoles that displace the nucleus to the periphery of the cell. Use of frozen sections and special stains is needed to document the contents of the vesicles as fat. Based on the size of the fat droplets, one can distinguish between macrovesicular and microvesicular steatosis. Currently, the most common cause of hepatic steatosis is insulin resistance due to central obesity and sedentary lifestyle. Compounds that produce prominent steatosis associated with lethality include the antiepileptic drug valproic acid (Scheffner et al. Ethanol is by far the most relevant drug or chemical leading to steatosis in humans and in experimental animals. Often, drug-induced steatosis is reversible and does not lead to death of hepatocytes. The metabolic inhibitors ethionine, puromycin, and cycloheximide cause fat accumulation without causing cell death. Although steatosis alone may be benign, it can develop into steatohepatitis (alcoholic or nonalcoholic), which is associated with significant liver injury (Farrell, 2002; Pessayre et al. Livers with steatosis are more susceptible to additional insults such as hepatotoxins (Donthamsetty et al. Fibrosis can develop around central veins and portal tracts or within the space of Disse. The excessive extracellular matrix protein deposition and the loss of sinusoidal endothelial cell fenestrae and of hepatocyte microvilli limit exhange of nutrients and waste material between hepatocytes and sinusoidal blood. With continuing collagen deposition, the architecture of the liver is disrupted by interconnecting fibrous scars. When the fibrous scars subdivide the remaining liver mass into nodules of regenerating hepatocytes, fibrosis has progressed to cirrhosis and the liver has limited residual capacity to perform its essential functions. The primary cause of hepatic fibrosis/cirrhosis in humans worldwide is viral hepatitis. However, biliary obstruction and in particular alcoholic and nonalcoholic steatohepatitis are of growing importance for the development of hepatic fibrosis (Bataller and Brenner, 2005).
