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Biomedical subjects

N Kaplowitz

Publications and source records attributed to N Kaplowitz.

At least 163 records · Page 9Linked to original sources
PubMed1978

Inhibition of hepatic metabolism of azathioprine in vivo.

Glutathione-mediated thiolysis of azathioprine in the liver is believed to be the main mechanism for the conversion of this drug to 6-mercaptopurine. This metabolic step was inhibited in vivo by pretreating rats with probenecid as indicated both by less hepatic glutathione depletion and by a greater proportion of unmetabolized azathioprine in the liver. Less hepatic gluthathione depletion was also found in the hyperbilirubinemic Gunn rat. These findings indicate that the conversion of azathioprine to 6-mercaptopurine in vovo is mediated enzymatically by the glutathione S-transferases.

Animals↗
PubMed1978

Aplastic anemia associated with type B viral hepatitis.

Aplastic anemia is a recognized complication of viral hepatitis, but, to our knowledge, no cases associated with type B hepatitis have been described. We report the case of a patient who developed severe aplastic anemia very early in the course of infection with hepatitis B virus.

Adult↗
PubMed1978

Significance of microscopic cholangitis in alcoholic liver disease.

Marked biochemical cholestasis mimicking extrahepatic obstruction may occur in alcoholic liver disease. Twenty-three consecutive hyperbilirubinemic alcoholics who underwent liver biopsy were studied. Comparison of the clinical, laboratory, and histological features was made between patients with no or rare intraductal polymorphonuclear leukocytes, group A (19 cases), and those with polymorphonuclear leukocytes in multiple bile ducts ("microscopic cholangitis"), group B (4 cases). Extrahepatic biliary obstruction was excluded in group B by cholangiography. Group B had significantly higher serum SGOT, bilirubin, alkaline phosphatase, and cholesterol than group A. All group B patients had periductal acute inflammation and severe panlobular cholestasis. However, there was no significant histological difference comparing group A patients with alkaline phosphatase greater than 300 mIU per ml and group B patients, except for the presence of intraductal polymorphonuclear inflammation. Therefore, we conclude that microscopic cholangitis is a feature of severe cholestasis which may accompany alcoholic liver injury.

Adult↗
PubMed1977

Endocrine and metabolic alterations with food and water deprivation.

Two healthy men were evaluated before and after a 56-day raft voyage to determine endocrine and metabolic status immediately after and during the recovery phase after long-term caloric, protein, and water deprivation. Daily intake during the trip consisted of no protein, 300 ml water, and for the first 40 days, 300 kcal glucose. The subjects lost weight from 84.1 to 58.1 and 78.3 to 57.7 kg, respectively. Significant variations included: 1) decreased excretion and loss of diurnal pattern of 17-hydroxycorticoids with normal serum corticoid levels and variation; 2) decreased serum testosterone levels and concomitant low follicle stimulating hormone and low normal luteinizing hormone levels; 3) decreased urinary 17-ketosteroid levels; 4) low plasma insulin levels with normal serum glucose concentrations; 5) increased triglyceride content in the 1.006 less than d less than 1.063 lipoproteins during fasting with a marked increase in high density lipoprotein cholesterol upon refeeding. The percent content of the R-serine (C-I) apoprotein among the soluble apoproteins of very low density lipoproteins diminished markedly during the fast; 6) abnormal liver function immediately after fasting with increased abnormality after the 2 weeks of refeeding and return to normal by 6 weeks; 7) normal fat and xylose absorption, normal estradiol, estrone and prolactin levels, and renal function studies.

Adult↗
PubMed1977

Metabolic clearance of furosemide in the rat.

The effect of probenecid on the metabolic clerance of [35S]furosemide was examined in Sprague-Dawley rats by the single injection technique. Metabolic clearance was found to decrease from 1.74+/-0.11 ml/min in animals which received furosemide alone to 1.06+/-0.10 ml/min in animals which received both furosemide and probenecid. Estimation of urine and biliary clearance revealed that approximately two-thirds of the metabolic clearance was due to urinary clearance and one-third to biliary clearance, and that both decreased after probenecid administration. Thin-layer chromatographic studies indicated furosemide was metabolized by both liver and kidney but also secreted in unchanged form in urine, and that the proportion of unaltered furosemide to metabolite in urine was increased by probenecid. Further studies indicated that phenobarbital pretreatment had no effect on either hepatic or renal clearance of furosemide and that bile clearance was not altered by acute bilateral nephrectomy.

Animals↗
PubMed1977

The glutathione S-transferases of the small intestine in the rat.

Glutathione S-transferase activities have been identified in the small intestine of the rat. Thrree activities obtained with p-nitrobenzyl chloride (aralkyl), 1,2-epoxy-3(p-nitrophenoxy)propane (epoxide), and ethacrynic acid (alkene) as substrates were present in significant amounts. Gel filtration indicated an elution volume for the intestinal transferase activities that was similar to those activities in the liver and kidney. The induction of the intestinal transferases by polycyclic aromatic hydrocarbons and phenobarbital is similar to those effects observed previously for the hepatic and renal enzymes. The highest concentration of transferase activities occurs in the proximal small intestine; these activities are reduced upon fasting. Parallel observations have been reported for aryl hydrocarbon hydroxylases. Because only low or negligible levels of epoxide hydrases have been reported in the small intestine, the glutathione S-transferases may be the primary epoxide-detoxifying system in that organ.

Animals↗
PubMed1977

Interaction of azathioprine and glutathione in the liver of the rat.

Azathioprine was administered to rats in order to study its interaction with glutathione in vivo. Glutathione levels were measured sequentially in liver, red blood cells, kidney and small intestine after i.p. injections of azathioprine (6.25-100 micronmol/100 g b.wt.). Five minutes after drug administration, dose-related selective depletion of hepatic glutathione up to 50% of control was observed. By 60 minutes 80% depletion of hepatic glutathione was observed. Red cell glutathione depletion was also observed but lagged behind hepatic changes. Five minutes after azathioprine administrations, no change in red cell glutathione was seen with all doses of azathioprine, but a dose-related increase in plasma 6-mercaptopurine and azathioprine was observed. At all azathioprine doses and at all time intervals after drug administration, the hepatic contribution to total glutathione consumption predominated. No change in glutathione levels in kidney or small intestine was observed after azathioprine. Thus, the liver plays a major role in the metabolism of azathioprine through the interaction of the drug with glutathione.

Animals↗
PubMed1976

Comparison of renal and hepatic glutathione S-transferases in the rat.

Renal and hepatic GSH (reduced glutathione) S-transferase were compared with respect to substrate and inhibitory kinetics and hormonal influences in vivo. An example of each of five classes of substrates (aryl, aralkyl, epoxide, alkyl and alkene) was used. In the gel filtration of renal or hepatic cytosol, an identical elution volume was found for all the transferase activities. Close correspondence in Km values was found for aryl, epoxide- and alkyl-transferase activities, with only the aralkyl activity significantly lower in kidney. Probenecid and p-aminohippurate were competitive inhibitors of renal aryl-, aralkyl-, epoxide- and alkyl-transferase activities and inhibited renal alkene activity. Close correspondence in Ki values for inhibition by probenecid of these activities in kidney and liver was found. In addition, furosemide was a potent competitive inhibitor of renal alkyl-transferase activity. Hypophysectomy resulted in significant increases in aryl-, araklyl-, and expoxide-transferase activities in liver and kidney. The hypophysectomy-induced increases in renal aryl- and aralkyl-transferase activities (approx. 100%) were more than twofold greater than increases in hepatic activities (approx. 40%). Administration of thyroxine prevented the hypophysectomy-induced increase in aryltransferase activity in both kidney and liver. The renal GSH S-transferases, in view of similarities to the hepatic activities, may play a role as cytoplasmic organic-anion receptors, as previously proposed for the hepatic enzymes.

Animals↗
PubMed1975

Drug induction of hepatic glutathione S-transferases in male and female rats*.

The induction of the glutathione S-transferases by phenobarbital and polycyclic hydrocarbons was studied in male and female rats. Administration of phenobarbital resulted in 60-80% increase in S-aryl and S-aralkyl enzyme specific activities, whereas the S-epoxide and S-alkyl activities were increased by 30-40%. In following the sequence of induction, the former two activities were noted to reach peak activities before an increase in the latter two activities was observed. Both 3-methylcholanthrene and 3,4-benzopyrene were shown toi nduce these four enzymic activities, although without the discrimination between pairs of activities noted with phenobarbital. No change in Km accompanied the increase in Vmax. after induction by drugs, and no change occurred in Ki for sulphobromophthalein inhibition. Significantly lower enzyme specific activities were found for three of the activities studied in female rats but no difference was observed in the S-alkyltransferase activity. However, the proportional increase in the enzymic activities in response to phenobarbital was the same in males and females. These studies demonstrate the drug induction of a group of cytosolic drug-metabolizing enzymes as well as the identification of sex differences in these activities.

Animals↗
PubMed1975

Drug induction and sex differences of renal glutathione S-transferases in the rat.

Treatment of male rats with 3,4-benzopyrene, 3-methylcholanthrene and phenobarbital resulted in the induction of glutathione S-aryl- and S-aralkyl-transferase activities in kidney cytosol. Benzopyrene produced 77 and 44% increases in aryl and aralkyl activities respectively. Methylcholanthrene caused 73 and 86% increases in the retrospective activities, whereas phenobarbital treatment increased only aralkyl activity (51%). There was no effect on epoxide or alkyl glutathione S-transferase activities with these treatments. Differences were found between the specific activities of the four glutathione S-transferases in females and males, with the following female/male ratios: aryl 0.74; aralkyl 2.37; epoxide 1.52; alkyl 1.33. No changes in Km values were observed relative to drug induction or sex differences. Comparisons are made between the findings of this report and corresponding experiements with liver.

Animals↗
PubMed1975

Hepatic glutathione S-transferases: identification by gel filtration and in vitro inhibition by organic anions.

In the gel filtration of 100,000 g rat liver supernatant, four major glutathione S-transferase activities, S-aryl-, S-epoxide-, S-aralykyl, and S-alkyltransferase, were identified as having an elution volume identical to that of fractions exhibiting either glutathione or sulfobromophthalein sodium binding. The organic anions, sulfobromophthalein sodium, indocyanine green, and bilirubin, were found to be competitive inhibitors of the four glutathione S-transferase activities. These findings indicate that the glutathione S-transferases bind organic anions, and as a group, have a similar molecular weight to a known organic anion-binding protein. It is proposed that these enzymes also serve nonenzymically as a group of binding proteins in the hepatic cytoplasmic transport of organic anions.

Animals↗
PubMed1973

Role of hepatic anion-binding protein in bromsulphthalein conjugation.

Using gel filtration, the binding of both glutathione and Bromsulphthalein (BSP) to a liver-soluble protein was found to be identical. BSP-conjugating activity (glutathione S-aryltransferase) was present only in the fractions corresponding to the two protein-bound markers. Using a highly sensitive assay, with 3,4-dichloronitrobenzene, the pattern of glutathione S-aryltransferase activity was found to coincide with Y protein. This evidence suggests that Y protein, or ligandin, has a dual role in hepatic transport: a specific enzymic function in the conjugation of certain anions with glutathione in addition to a transport function in the intracellular binding of organic anions.

Animals↗
PubMed1973

Quantitative analysis of unconjugated and conjugated bile acids in duodenal fluid by densitometry after paper electrophoresis.

A new paper electrophoretic method for the separation of bile acids into five groups, (1) unconjugated, (2) glycine conjugates and (3) taurine conjugates, and (4) and (5) the respective monosulfates, is described. Rapid and accurate qualitative and quantitative estimations of each group are obtained by densitometry after internal standardization and phosphomolybdate color development. The technique can be done in the routine clinical laboratory and is useful for the detection of diseases affecting the enterohepatic circulation of bile acids.

Bile Acids and Salts↗