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Biomedical subjects

K W Bock

Publications and source records attributed to K W Bock.

At least 127 records · Page 7Linked to original sources
PubMed1978

Increase of liver microsomal benzo(a)pyrene monooxygenase activity by subsequent glucuronidation.

Benzo(a)pyrene monooxygenase activity in rat and guinea pig liver microsomes is markedly stimulated when UDP-glucuronic acid is present in the assay. This effect is further enhanced by addition of UDP-N-acetylglucosamine, an allosteric activator of UDP-glucuronyltransferase. The results suggest a coupling between microsomal monooxygenase and UDP-glucuronyltransferase which may assist elimination of toxic compounds.

Animals↗
PubMed1977

Dual role of glucuronyl- and sulfotransferases converting xenobiotics into reactive or biologically inactive and easily excretable compounds.

Glucuronyl- and sulfotransferases inactivate a wide variety of hazardous compounds, for example, phenols and dihydrodiols generated during the metabolism of polycyclic hydrocarbons. Our understanding of the firmly membrane-bound glucuronyltransferase is complicated because of their marked activation by membrane perturbants in vitro. Membrane perturbation also occurs in vivo, for example in liver injury caused by CCl4. Moreover, glucuronyltransferases are inducible by xenobiotics. Phenobarbital and 3-methylcholanthrene probably stimulate separate glucuronyltransferases. Sulfotransferases, located in the cytoplasm, often compete with glucuronyltransferases for the same substrates. The generation of 'active sulfate' (PAPS) from cysteine is more likely to be depleted in vivo than the formation of UDP-glucuronic acid generated from carbohydrates. Hence the proportion of sulfate ester/glucuronide may fall with increasing dose of the substrate. Sulfate esters and glucuronides of certain N-hydroxy-arylamines (N-hydroxy-N-acetylaminofluorene, N-hydroxy-phenacetin) are more reactive than the parent compound and bind covalently to cell constituents. Of the two conjugates, sulfate esters are more reactive and thereby more toxic than the corresponding glucuronides. Glucuronides may become toxic in the kidney and bladder where they are highly concentrated.

Animals↗
PubMed1977

UDP-glucuronyltransferase in perfused rat liver and in microsomes. Effects of CCl4 injury.

To elucidate the disparity between glucuronidation rates in vivo and UDP-glucuronyltransferase in vitro after CCl4 injury, the time course of the effects of CCl4 (0.25 ml/kg) on kinetic properties of UDP-glucuronyltransferase (l-naphthol as substrate) was examined in rat liver homogenates and microsomes. These experiments were compared with l-naphthol glucuronidation by the perfused liver which was studied at various time points after CCl4 administration. Phenobarbital-treated rats were used to enhance the hepatotoxicity of CCl4. 1. Within 24 h UDP-glucuronyltransferase activity increased 8-fold in liver homogenates and 3-fold in microsomes. During this time the allosteric activator, UDP-N-acetylglucosamine, lost its effect whereas the inhibitor UPD showed greater inhibitory properties, thus counteracting the activation. 2. l-Naphthol glucuronidation in perfused livers was significantly decreased by 24 h. Sulfate ester formation was little affected. 3. The content of UDP-glucuronic acid was not significantly altered although liver histology revealed about 45% necrotic and prenecrotic cells and an uniform fatty degeneration of hepatocytes after 24 h. The results suggest that during CCl4 injury, UDP-glucuronyltransferase is activated. At the same time the kinetic properties of the enzyme are altered in a way leading to inefficient glucuronide synthesis, when assays are carried out under conditions presumed to exist in vivo. Nevertheless the capacity to form glucuronides is retained in the acutely injured liver.

Animals↗
PubMed1976

UDP-glucuronyltransferase in perfused rat liver and in microsomes. Glucuronidation of bilirubin.

In perfused rat liver and in fistula rats the formation of bilirubin conjugates was studied after labeling with [14C]bilirubin,5-amino [14C]levulinic acid and [14C]hemin. The latter two compounds were used to study heme degradation to bilirubin from intrahepatic and extrahepatic sources, respectively. Bilirubin glucuronides were the major conjugates in fistula bile. In liver perfusion bile the proportion of non-glucuronide conjugates was increased. After a high dose of hemin (2.5 mumol) bilirubin glucuronides were decreased compared with other bilirubin conjugates both in fistula bile and in liver perfusion bile. In addition green pigments were formed. These alterations were reversed in chronically hemin-treated rats in which heme oxygenase had been induced. The interference of UDP-glucose and UDP-glucuronic acid with bilirubin glucuronidation and glucosidation was studied in liver microsomes. UDP-glucose did not affect bilirubin glucuronidation in native microsomes in which UDP-glucuronyltransferase activity is constrained. When this constraint was released by various treatments altering membrane structure UDP-glucose markedly inhibited bilirubin glucuronidation. However, under these conditions bilirubin glucosidation was unaffected by UDP-glucuronic acid. The results suggest that the release of the constraint of UDP-glucuronyltransferase in vivo may lead to a decrease of the proportion of bilirubin glucuronides to other bilirubin conjugates in bile.

Aminolevulinic Acid↗
PubMed1976

Lack of glucose effect on the induction of 5-aminolevulinate synthetase and tyrosine aminotransferase in the isolated perfused rat liver.

In the isolated perfused rat liver, both 5-aminolevulinate synthetase and tyrosine aminotransferase were induced by the addition of 3.5 mmol/l allylisopropylacetamide and 58 mumol/l dexamethasone to the perfusion medium. Glucose (40 mmol/l) did not affect either the induction of these enzymes or the intrahepatic level of cyclic AMP. The results suggest that the glucose effect on the induction of 5-aminolevulinate synthetase and tyrosine aminotransferase in vivo is mediated by extrahepatic factors.

5-Aminolevulinate Synthetase↗
PubMed1975

Relationship between microsomal hydroxylase and glucuronyltransferase.

These experiments did not answer the question of whether one or several UDG-glucuronyltransferases are present in endoplasmic membranes of the liver. However, they present results which indicate that the glucuronlytransferase (s) have several properties in common with the hydroxylating cytochrome P-450 dependent enzyme system: the inducibility (which differs considerably after pretreatment with phenobarbital or 3-methylcholanthrene), the sex specificity, and the inhibition by the same compounds. The most obvious difference between the systems is the alteration of the enzyme activities after solubilization of the membranes by sonication or use of detergents.. On solubilization, the activity of the glucuronyltransferase (s) increases, whereas the opposite is true for the hydroxylating system which may lose one or several components essential for its activity (such as the NADPH dependent reductase). Our experiments can best be interpreted by assuming a common micro-environment around the enzymes produced by lipids and proteins which modulate both the rate of hydroxylation and that of glucuronyl-conjugation of drugs.

Aminopyrine↗