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N Kaplowitz

Publications and source records attributed to N Kaplowitz.

At least 145 records · Page 8Linked to original sources
PubMed1981

Direct protection against acetaminophen hepatotoxicity by propylthiouracil. In vivo and in vitro studies in rats and mice.

Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [(3)H]acetaminophen, liver microsomes from phenobarbital-pretreated rats, and an NADPH-generating system, we found that PTU had a dose-dependent additive effect with GSH on inhibition of acetaminophen covalent binding. PTU administration also resulted in a dose-dependent decrease in both GSH depletion and covalent binding in vivo in acetaminophen-treated mice. To examine the possible mechanisms by which PTU exerts its protective effect, we studied the action of PTU on both acetaminophen conjugation and metabolic activation. PTU had no effect upon acetaminophen pharmacokinetics in phenobarbital-pretreated rats, as examined by measuring acetaminophen concentration in bile, urine, and blood after an intraperitoneal dose, nor did it alter the total amount of polar conjugates formed. Microsomes from PTU-treated rats were unaltered in cytochrome P-450 concentrations and p-nitroanisole-O-demethylase, benzo-alpha-pyrene hydroxylase, and cytochrome c-reductase activities. Furthermore PTU did not decrease acetaminophen-GSH adduct formation in vitro, suggesting that there was no reduction in drug activation. However, in bile from [(35)S]PTU and [(3)H]acetaminophen treated rats, as well as in incubates of the two drugs with liver microsomes, a new (35)S- and (3)H-containing product could be identified. By both thin layer chromatography and high pressure liquid chromatography this new product, which co-eluted with [(3)H]acetaminophen, was separated from unreacted [(35)S]PTU. The formation of this product in vitro was a function of PTU concentration and reached a maximum of 0.06 mumol/min per mg protein at 0.5 mM PTU. In vivo, the total biliary excretion of this product over 4 h (116 nmol) equaled the net reduction in acetaminophen metabolite covalent binding in the liver of phenobarbital-pretreated rats (108 nmol). We conclude that PTU, independent of its antithyroid effect, diminishes hepatic macromolecular covalent binding of acetaminophen reactive metabolite both in vivo and in vitro, and it does so by detoxifying the reactive metabolite through direct chemical interaction in a manner similar to GSH. These observations may define the mechanism by which PTU is protective against liver injury caused by acetaminophen.

Acetaminophen↗
PubMed1980

Physiological significance of glutathione S-transferases.

The glutathione S-transferases represent a group of closely related soluble enzymes that seem geared to detoxification. These enzymes, which are most abundant in the liver but are found in most cells, catalyze the interaction between glutathione and a broad spectrum of electrophilic reactive drugs, carcinogens, and metabolites. In addition, a more speculative aspect of the detoxification role of these proteins is the covalent interaction between certain reactive carcinogen metabolites and the enzymes. Finally, as an aspect of their broad specificity, the transferases bind a broad spectrum of nonsubstrate ligands including bilirubin. On this basis a role in hepatic organic anion transport has been proposed for the transferases (previously known as Y protein or ligandin). It is now recognized that the transferases may affect net uptake by the liver by minimizing back diffusion. Much work remains to more precisely define the regulation and role(s) of this enzyme system in vivo.

Animals↗
PubMed1980

Effect of salicylates and phenobarbital on hepatic glutathione in the rat.

Phenobarbital and salicylates were shown to have opposite effects on hepatic glutathione. Phenobarbital increased glutathione concentration by approximately 20 to 30%. This increase occurred within 48 hr and could be attributed almost exclusively to an increase in bound glutathione. No changes in ATP, substrate amino acids for glutathione synthesis or the level of gamma-glutamylcysteine synthetase, the rate limiting enzymatic step in glutathione synthesis, were found with phenobarbital. Phenobarbital, which induces hepatic proteins that bind glutathione, increased bound glutathione but did not affect unbound glutathione. Therefore, the concentration of the latter probably regulates glutathione synthesis. Salicylates (aspirin and sodium salicylate) were found to deplete hepatic glutathione in both saline- and phenobarbital-treated rats. Maximum depletion (approximately 40%) was seen 4 to 6 hr after salicylate administration and returned toward the control level by 12 hr. The salicylate effect was not related to a change in gamma-glutamylcysteine synthetase, gamma-glutamyl transpeptidase or the concentrations of free hepatic glycine, glutamate, cysteine and methionine. An increase in concentration of glutathione both in vivo in plasma from salicylate-treated rats and in vitro in buffer from the incubation of liver slices with salicylate suggests that glutathione leakage from hepatocytes is an important factor in salicylate-induced hepatic glutathione depletion.

Amino Acids↗
PubMed1979

Common bile duct stenosis from chronic pancreatitis: a clinical and pathologic spectrum.

The chronic pancreatitis population of Wadsworth VA Hospital over the past five years was screened for two-fold or greater alkaline phosphatase elevation at any time during their course, as a marker for either distal common bile duct stenosis or other hepatobiliary disease. Forty-seven of 207 patients screened met this criterion and are reviewed in detail. Of the 16 patients with persistent alkaline phosphatase elevation (group B), 15 had proven common bile duct stenosis, demonstrating a clear pathophysiologic role of partial bile duct obstruction in their liver disease. Three had developed secondary biliary cirrhosis, marking this entity the commonest cause of secondary biliary cirrhosis at our hospital. Of the remaining 31 patients with transient alkaline phosphatase elevation (group A), only 4 had proven duct abnormalities which may resolve during recovery. Alcoholic liver disease was demonstrated with normal extrahepatic ducts in the remainder in group A adequately studies. Persistent greater than two-fold alkaline phosphatase elevation in pancreatitis thus represents a reliable marker of distal common bile duct stenosis, whose sequelae may include cholangitis and secondary biliary cirrhosis and which requires operative intervention in these cases. When a persistent alkaline phosphatase elevation greater than two-fold is encountered in a chronic pancreatitis patient, adequate cholangiography and liver histology are both necessary to confirm and grade this frequent and treatable complication.

Alcoholism↗
PubMed1978

Glutathione S-transferase in human lymphoid cell lines and fractionated peripheral leucocytes.

Glutathione S-transferase activity was identified in cytosol from human lymphoid-cell lines and peripheral leucocytes (polymorphonuclear-leucocyte/monocyte and small-lymphocyte fractions) and compared with human liver enzyme. The findings of closely similar elution volume in gel filtration, substrate (1-chloro-2,4-dinitrobenzene) and inhibitory (probenecid) kinetics indicate that the liver, leucocyte and lymphoid-cell transferases are closely related. The interaction of reduced glutathione and 1-chloro-2,4-dinitrobenzene was shown to occur in intact-lymphoid-cell culture, to be linear with time and quantity of cells and to have kinetics similar to those of the enzyme reaction catalysed by cytosol.

Cell Line↗
PubMed1978

Obstructive jaundice caused by hepatocellular carcinoma. Report of three cases.

A cholestatic syndrome secondary to extrahepatic biliary obstruction as the presenting manifestation of hepatocellular carcinoma is described in three cases. The mechanism is related to the invasion of intrahepatic bile ducts by the carcinoma. The consequent mechanical obstruction is due to either a continuous distally growing tumor cast of the biliary tree, distal migration of a necrotic tumor fragment, or hemobilia. In the cirrhotic patient with a predisposition for the development of liver cancer, the physician should be aware of the presentation with obstructive jaundice as a mechanical complication of hepatocellular carcinoma.

Adolescent↗