Biotransformation and Zonal Toxicity

Thurman, Ronald G.; Kauffman, Frederick C.; Baron, Jeffrey

doi:10.1007/978-1-4684-5041-5_13

Cited by 25 publications

(8 citation statements)

References 170 publications

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“…of techniques: Histochemistry and immunohistochemistry in 5 to 20 pm native section^^^-'^ (Figure l), microbiochemical analyses in lyophilized microdissected tissue s e c t i~n s , l~-~~ and more recently digitonin pulse p e r f~s i o n .~~.~~ The distribution of subcellular structures has been determined using electron microscopic morp h~m e t r y .~~ Early histochemical and morphometric studies had revealed that hepatocytes from the periportal and the perivenous zone of the parenchyma differ in their content of enzymes and subcellular struct u r e~~~,~~,~~ Moreover, the zonal toxicity of xenobiotics had been a well-known phenomenon for a long time.28 In subsequent years the initial descriptive data on heterogeneity developed to a more functional understanding. [1][2][3][4][5][6][7][8][9]29,30 Based on the assumption that the zonal distribution of enzyme activities and subcellular structures are indicators of metabolic capacities, different functions for the two major zones of the parenchyma were proposed first for carbohydrate metabolism31 and later also for many other processes. This proposal became known as the model of "metabolic zonation"31 ( Table 1).…”

Section: Zonation Of Enzyme Content and Subcellularstructuresmentioning

confidence: 99%

Metabolic Zonation of Liver Parenchyma

Jungermann¹

1988

Semin Liver Dis

139

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Periportal and perivenous hepatocytes differ in their content of enzymes and subcellular structures and thus in their metabolic capacities. Therefore, the model of metabolic zonation proposes that: (1) periportal hepatocytes catalyze predominantly oxidative energy metabolism with beta-oxidation and amino acid catabolism as well as ureagenesis for glycogen synthesis and glucose release, bile formation with cholesterol synthesis and protective metabolism; and (2) perivenous hepatocytes mediate preferentially glucose uptake for glycogen synthesis, glycolysis, and liponeogenesis as well as ketogenesis, glutamine formation, and xenobiotic metabolism. Periportal and perivenous hepatocytes are under the control of a different input of humoral and nervous signals, because concentration gradients of oxygen, substrates, and hormones are established during passage of blood through the liver and because gradients of nerve densities seem to exist. In periportal and perivenous hepatocytes gene expression can be different due to the zonal gradients in oxygen and hormone concentrations as well as nerve densities. The functional specialization of periportal and perivenous hepatocytes has been demonstrated especially well for carbohydrate, amino acid and ammonia, and xenobiotic metabolism as well as for bile formation by different techniques: Calculation of metabolic rates based on the zonal distributions of enzymes and metabolites, measurements of rates in periportal-like and perivenous-like hepatocytes in cell culture and in hepatocyte populations enriched in periportal and perivenous cells as well as in perfused livers during orthograde and retrograde flow using standard methods and noninvasive techniques with surface microlight guides and miniature oxygen electrodes.

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Section: Zonation Of Enzyme Content and Subcellularstructuresmentioning

confidence: 99%

Metabolic Zonation of Liver Parenchyma

Jungermann¹

1988

Semin Liver Dis

139

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“…Much evidence indicates that xenobiotics can generate reactive oxygen species, including superoxide anion (O 2 · -), hydrogen peroxide (H 2 O 2 ), hydroxyl radical ( · OH), and singlet oxygen (O 2 1 ), which in turn are responsible for cell and tissue damage associated with different pathologic processes, including mutagenesis and carcinogenesis (5). Recently, oxidative stress and some parameters of fish antioxidant defenses and biotransformation enzymes (i.e., cytochrome P-450 1A1 and glutathione S-transferase, GST) of fish and molluscs have been used as biomarkers of water pollution (6)(7)(8)(9)(10)(11). Although the seasonal interference with the antioxidant defense system has not been well established in these organisms, the data available in the literature (12)(13)(14) suggest a general antioxidant defense enhancement during spring and summer when compared to low temperature periods.…”

Section: Introductionmentioning

confidence: 99%

Influence of season and pollution on the antioxidant defenses of the cichlid fish acará (Geophagus brasiliensis)

Filho

Torres

Tribess

et al. 2001

Braz J Med Biol Res

148

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The livers of Geophagus brasiliensis collected from both a nonpolluted site and a polluted site were analyzed for different antioxidant defenses, O 2 consumption, thiobarbituric acid-reactive substance (TBARS) levels, and histological damage. Compared to controls (116.6 ± 26.1 nmol g -1 ), TBARS levels were enhanced at the polluted site (284.2 ± 25.6 nmol g -1 ), as also was oxygen consumption (86.6 ± 11.3 and 128.5 ± 9.8 µmol O 2 min -1 g -1 , respectively). With respect to enzymatic antioxidants, increased catalase activities (8.7 ± 1.3 and 29.2 ± 2.4 mmol min -1 g -1 , respectively), unchanged superoxide dismutase activities (767.2 ± 113.3 and 563.3 ± 70.2 U g -1 , respectively), and diminished glutathione S-transferase activities (29.0 ± 3.2 and 14.9 ± 3.2 µmol min -1 g -1 , respectively) were detected. Reduced glutathione (1.91 ± 0.17 and 1.37 ± 0.25 mM, respectively), oxidized glutathione (1.50 ± 0.20 and 0.73 ± 0.17 mM, respectively), and total glutathione (3.40 ± 0.26 and 2.07 ± 0.27 mM, respectively) concentrations were also below control values at the polluted site. Nevertheless, the observed ethoxyresorufin-O-deethylase activities (1.34 ± 0.11 and 16.7 ± 0.21 pmol min -1 mg -1 , respectively) showed enhanced values at the polluted site. The main histological damage observed in the hepatocytes from fish collected at the polluted site was characterized by heavy lipid infiltration. Fish collected at the end of spring showed higher O 2 consumption, higher superoxide dismutase and glutathione S-transferase activities, and higher total and oxidized glutathione concentrations compared to the beginning of autumn. No seasonal changes were observed in catalase activities, glutathione or TBARS levels. Fish chronically exposed to relatively high pollution levels seem to be unable to set up adequate antioxidant defenses, probably due to severe injury to their hepatocytes. The higher antioxidant defenses found at the end of spring are probably related to the enhanced activities during high temperature periods in thermoconforming organisms.

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“…Later, the model was ex panded to include also amino acid and am monia metabolism, xenobiotic metabolism, protective metabolism and bile formation [7][8][9]. Reversal of lobular flux rates by changing the direction of flow demonstrated that short-term regulatory mechanisms are operative [8] (see subsection 'Differences of opinion...').Functional hepatocyte heterogeneity has been reviewed both in general [8][9][10][11][12] and with particular focus on the metabolism of carbohydrates [13,14], lipids [15,16], amino acids and ammonia [17,18], xenobiotics [19,20] or bile acids [21] as well as development [22], The present article at tempts to summarize the present view on the significance of liver cell heterogeneity in the regulation of glycogen metabolism, gluco neogenesis and glycolysis. …”

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confidence: 99%

Hepatocyte Heterogeneity in the Metabolism of Carbohydrates

Jungermann

Thurman²

1992

Enzyme

Self Cite

109

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Periportal and perivenous hepatocytes possess different amounts and activities of the rate-generating enzymes of carbohydrate and oxidative energy metabolism and thus different metabolic capacities. This is the basis of the model of metabolic zonation, according to which periportal cells catalyze predominantly the oxidative catabolism of fatty and amino acids as well as glucose release and glycogen formation via gluconeogenesis, and perivenous cells carry out preferentially glucose uptake for glycogen synthesis and glycolysis coupled to liponeogenesis. The input of humoral and nervous signals into the periportal and perivenous zones is different; gradients of oxygen, substrates and products, hormones and mediators and nerve densities exist which are important not only for the short-term regulation of carbohydrate metabolism but also for the long-term regulation of zonal gene expression. The specialization of periportal and perivenous hepatocytes in carbohydrate metabolism has been well characterized. In vivo evidence is provided by the complex metabolic situation termed the ‘glucose paradox’ and by zonal flux differences calculated on the basis of the distribution of enzymes and metabolites. In vitro evidence is given by the different flux rates determined with classical invasive techniques, e.g. in periportal-like and perivenouslike hepatocytes in cell culture, in periportal- and perivenous-enriched hepatocyte populations and in perfused livers during orthograde and retrograde flow, as well as with noninvasive techniques using miniature oxygen electrodes, e.g. in livers perfused in either direction. Differences of opinion in the interpretation of studies with invasive and noninvasive techniques by the authors are discussed. The declining gradient in oxygen concentrations, the decreasing glucagon/insulin ratio and the different innervation could be important factors in the zonal expression of the genes of carbohydrate-metabolizing enzymes. While it is clear that the hepatocytes sense the glucagon/insulin gradients via the respective hormone receptors, it is not known how they sense different oxygen tensions; the O(2) sensor may be an oxygen-binding heme protein. The zonal separation of glucose release and uptake appears to be important for the liver to operate as a ‘glucostat’. Thus, zonation of carbohydrate metabolism develops gradually during the first weeks of life, in part before and in part with weaning, when (in rat and mouse) the fat- and protein-rich but carbohydrate-poor nutrition via milk is replaced by carbohydrate-rich food. Similarly, zonation of carbohydrate metabolism adapts to longer lasting alterations in the need of a ‘glucostat’, such as starvation, diabetes, portocaval anastomoses or partial hepatectomy.

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Biotransformation and Zonal Toxicity

Cited by 25 publications

References 170 publications

Metabolic Zonation of Liver Parenchyma

Metabolic Zonation of Liver Parenchyma

Influence of season and pollution on the antioxidant defenses of the cichlid fish acará (Geophagus brasiliensis)

Hepatocyte Heterogeneity in the Metabolism of Carbohydrates

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