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At least 19 recordsLinked to original sources
PubMed1992

Endotoxin tolerance and polymyxin B modify liver damage and cholestasis induced by a single dose of alpha-naphthylisothiocyanate in the rat.

A single oral dose of alpha-naphthylisothiocyanate (ANIT) induces intrahepatic cholestasis and endotoxemia in the rat. To assess if a pathogenic relationship between endotoxin and ANIT-induced liver injury could be postulated, rats were pretreated by either induction of endotoxin tolerance, or with the anti-endotoxin agent polymyxin B. A single oral dose (10 or 20 mg/100 g body wt) of ANIT was then given to ascertain whether these methods of modifying endotoxicity would protect the animals against ANIT damage. Both pretreatments significantly reduced the incidence of endotoxemia after ANIT administration, as detected by either lead acetate enhancement method or the Limulus gelation test (LGT). The lethality of a single 20 mg/100 g body wt dose of ANIT was reduced from 55% to 15% by polymyxin B administration, and to 10% by an endotoxin-tolerant state. Moreover, when 10 mg/100 g body wt ANIT was given none of the animals died in 10 days, and the serum levels of bilirubin, alkaline phosphatase (AlPh), gamma-glutamyl transferase (gamma-GT), and transaminases (evaluated 1, 2, and 5 days after treatments) were significantly lower in the endotoxin-tolerant or polymyxin B administered rats; this biochemical protection was mirrored in the lack of histological alteration. The results demonstrate that the modification of endotoxicity offers significant protection against acute liver damage induced by ANIT. Thus the development of endotoxemia may play a pathogenic role in ANIT-induced liver injury. This conclusion is supportive of the hypothesis that endotoxins are necessary for the hepatotoxic agent to exert its full effects.

1-Naphthylisothiocyanate↗
PubMed1991

Distribution of glucose-6-phosphatase activity in normal, hyperplastic, and preneoplastic rat liver.

The significance of glucose-6-phosphatase (G6P) expression by bile duct-like cells proliferating during hepatocarcinogenesis in the histogenesis of hepatocellular carcinoma is not clear. To this end, we measured the histochemical and biochemical activity of G6P in normal rat liver, and in rat livers in which bile duct-like proliferation was induced by either hyperplastic (bile duct ligation for 14 days or feeding alpha-naphthylisothiocyanate for 28 days) or neoplastic (feeding a choline-devoid diet containing 0.1% ethionine for 60 days) regimens. In normal, hyperplastic, and preneoplastic livers, G6P histochemical activity was confined to the hepatocytes; proliferated bile duct-like cells, like normal bile ducts, did not display visible G6P staining. When the enzyme activity was determined biochemically, however, hydrolysis of glucose-6-phosphate was observed in both parenchymal and nonparenchymal liver cells isolated from all experimental animals. In elutriated nonparenchymal fractions, G6P activity was directly proportional to the number of cells positive for gamma-glutamyl transpeptidase and cytokeratin no. 19 (markers of bile duct cells) and inversely proportional to the number of cells positive for vimentin (marker of mesenchymal cells). These results indicate that, while by light microscopy hepatic G6P histochemical activity is detectable only in the hepatocytes, the biochemical activity is also expressed in proliferating bile duct-like cells. However, the nonparenchymal activity is observed during both neoplastic and hyperplastic liver growth, thus indicating that the presence of this enzyme in bile duct-like cells proliferating during hepatocarcinogenesis should not necessarily be construed as supporting their stem cell nature nor their neoplastic commitment.

1-Naphthylisothiocyanate↗
PubMed1991

Protection against alpha-naphthylisothiocyanate-induced liver injury by decreased hepatic non-protein sulfhydryl content.

alpha-Naphthylisothiocyanate (ANIT) injures bile duct epithelium and hepatic parenchymal cells in rats. It is commonly believed that ANIT must undergo bioactivation by hepatic, cytochrome P450-dependent mixed-function oxidases (MFO), since agents which are inducers or inhibitors of hepatic MFO activity enhance or attenuate, respectively, the liver injury associated with ANIT. Several of these agents also affect hepatic glutathione (GSH) content and/or GSH S-transferase activity in a manner to suggest a causal role for GSH in ANIT-induced hepatotoxicity. To determine whether GSH might be involved in the mechanism of injury, buthionine sulfoximine (BSO), diethyl maleate (DEM), or phorone was used to reduce hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content. Twenty-four hours after ANIT treatment, rats exhibited cholestasis and elevations in serum of total bilirubin concentration, total bile acid concentration, aspartate aminotransferase (AST) activity, and gamma-glutamyltransferase activity. Cotreatment of rats with BSO decreased NPSH content by 70% at 24 hr and prevented the cholestasis and elevations in serum markers of liver injury caused by ANIT. Likewise, cotreatment of rats with DEM afforded protection against markers of liver injury. Phorone treatment attenuated ANIT-induced elevations in serum total bilirubin concentration and AST activity. Although BSO treatment afforded protection against ANIT-induced liver injury at 24 hr, the injury was evident at 48 hr, and it appeared to coincide with a return of hepatic NPSH content. These results suggest that GSH plays a causal or permissive role in the liver injury caused by ANIT.

1-Naphthylisothiocyanate↗
PubMed1991

Relationship between alpha-naphthylisothiocyanate-induced liver injury and elevations in hepatic non-protein sulfhydryl content.

Acute administration of alpha-naphthylisothiocyanate (ANIT) to rats has been used as a model of intrahepatic cholestasis. The mechanism of toxicity of ANIT is unknown, although recent evidence suggests a causal or permissive role for glutathione (GSH) (Dahm LJ and Roth RA, Biochem Pharmacol 42: 1181-1188, 1991). In these studies, ANIT treatment elevated hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content, when liver injury was evident. The purpose of the present study was to characterize the effects of ANIT on hepatic NPSH content and to relate these changes to the development of liver injury. In rats fasted for 24 hr, administration of ANIT (100 mg/kg, per os [p.o.]) did not change hepatic NPSH content, bile flow, or serum measurements of total bilirubin concentration, alanine aminotransferase (ALT) activity, or gamma-glutamyltransferase (GGT) activity by 12 hr post-treatment relative to corn oil vehicle controls. However, by 24 hr after ANIT treatment, rats exhibited cholestasis and elevations in serum markers of liver injury. These markers were associated temporally with an increase in hepatic NPSH content, which consisted entirely of GSH. To determine whether the cholestasis caused by ANIT treatment might have caused the elevation of hepatic NPSH content, an extrahepatic cholestasis in rats was produced by ligation of the common bile duct. Bile duct ligation elevated hepatic NPSH content between 6 and 12 hr after ligation. Administration to rats of a non-hepatotoxic analog of ANIT, beta-naphthylisothiocyanate, also elevated hepatic NPSH content 24 hr after treatment. Taken together, these results indicate that the elevation in hepatic NPSH content after ANIT treatment is associated temporally with the onset of liver injury, but this elevation does not appear to participate causally in the mechanism of injury.

1-Naphthylisothiocyanate↗
PubMed1977

A methionine-reversible folate deficiency in rats following the acute administration of diethylnitrosamine and alpha-naphthylisothiocyanate.

Acute doses of the hepatotoxic agents diethylnitrosamine (DEN) and alpha-naphthylisothiocyanate (ANIT) to young adult male rats led to the production of a folate deficiency as determined by an elevated urinary excretion of formiminoglutamic acid (FIGLU) 2 to 4 days following administration of the compounds. High dietary levels of methionine significantly reduced the elevated levels of FIGLU produced by the 2 chemicals. Dietary folate had no significant effect on the excretion of urinary FIGLU. Although the hepatic levels of S-adenosylmethionine (SAM) were significantly increased in rats fed the high dietary levels of methionine, an acute dose of DEN did not depress the hepatic levels of SAM. The results indicate that the methyl-reversible folate deficiency caused by hepatotoxic agents is not the direct consequence of altered hepatic levels of SAM.

1-Naphthylisothiocyanate↗
PubMed1979

Reflux of billiary components into blood in experimental intrahepatic cholestasis induced in rats by treatment with alpha-naphthylisothiocyanate.

The sera of rats treated with alpha-naphthylisothiocyanate, an agent reported to cause intrahepatic cholestasis, and of rats treated with carbon tetrachloride, are examined for evidence of leakage of bile into blood. The levels of the four bile components assayed, namely IgA, free IgA secretory component, the biliary isoenzyme of 5'-nucleotidase and of direct reacting (conjugated) bilirubin, were all elevated in the sera of rats treated with alpha-naphthylisothiocyanate. No change in any of these components was found in rats treated with carbon tetrachloride, indicating that their appearance in serum is not an inevitable consequence of damage to hepatocytes. As the bile components assayed reach bile by three different routes. their rapid appearance in the sera of rats treated with alpha-naphthylisothiocyanate indicates reflux of bile into blood, presumably as a result of mechanical obstruction of intraheptic bile ducts.

1-Naphthylisothiocyanate↗
PubMed1991

The differential effects of hepatotoxicants on the sulfation pathway in rats.

This study characterized the effects of liver damage produced by a variety of hepatotoxicants on several components of the sulfation pathway in rats. Specifically, the concentration of cosubstrate, adenosine 3'-phosphate 5'-phosphosulfate (PAPS), and the hepatic capacity for PAPS synthesis were measured in livers of rats treated with carbon tetrachloride (CCl4), 1,1-dichloroethylene (DCE), alpha-naphthylisothiocyanate (ANIT), aflatoxin B1 (ATX), allyl alcohol (AA), bromobenzene (BB), cadmium chloride (Cd), or thioacetamide (TA). Liver damage was assessed by measuring serum sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALT) activities as well as by histopathological examination. Hepatic PAPS concentration was generally decreased as a result of treatment with hepatotoxicants (35-80% of control), although BB, AA, and ANIT were without effect. Maximal hepatic capacity for PAPS synthesis, determined as the activities of PAPS synthetic enzymes, ATP sulfurylase, and APS kinase, was selectively decreased by the hepatotoxicants. ATP sulfurylase activity was decreased by Cd and TA (55 and 62% of control, respectively), whereas APS kinase activity was decreased by Cd, TA, BB, and DCE (60-77% of control, respectively). In addition, phenol sulfotransferase (PST) activity was measured toward 1- and 2-naphthol in order to determine whether apparent changes in PST activity in damaged livers are substrate-dependent. Treatment with hepatotoxicants generally decreased 1-naphthol-directed PST activity but not PST activity directed toward 2-naphthol. In conclusion, (1) not all xenobiotic-induced liver injury results in decreased hepatic PAPS concentration, (2) some hepatotoxicants decrease PAPS concentration by a mechanism other than decreased cosubstrate synthesis, and (3) the effect of hepatotoxicants on PST activity is dependent upon the choice of substrate used in the enzymatic assay.

1-Naphthylisothiocyanate↗
PubMedDate not supplied

Effect of drugs on progesterone metabolism in the female rat.

Various drugs brought about a reduction of serum progesterone level irrespective of whether or not a potent inducer (phenobarbital, 4-methyl-coumarin) or a hepatotoxin (carbon tetrachloride, alpha-naphthylisothiocyanate, coumarin) has been administered. The decrease by hepatotoxins was highly significant during the estrus phase of the cycle. These treatments affected the hepatic level of progesterone and altered the uptake of [4-14C]progesterone in vivo. The serum level of progesterone was significantly decreased by phenobarbital and carbon tetrachloride; however, the incorporation into the liver was enhanced by phenobarbital and reduced by carbon tetrachloride. This opposing hepatic action showed selectivity; phenobarbital increased the oxidative pathway of progesterone metabolism (formation of 6 beta-, 16 alpha-, 20 alpha-hydroxyprogesterone) but the reductive pathway remained unaltered (formation of pregnanediol, pregnanolone). Conversely, carbon tetrachloride diminished oxidation and raised reduction of progesterone. These results have been confirmed by measurements of progesterone metabolism in vitro using isolated microsomes. Phenobarbital brought about an induction of progesterone 16 alpha-, 6 beta- and 20 alpha-hydroxylase, did not affect progesterone delta 4-5 alpha-dehydrogenase, whereas carbon tetrachloride inhibited hydroxylase and raised dehydrogenase activities. The action of these test compounds on serum and liver levels of progesterone and on the variation of progesterone metabolism seemed to be related to changes manifest in the function of the hepatic endoplasmic reticulum. Similar changes might be associated with the development of mild hepatic lesions induced by various steroids.

1-Naphthylisothiocyanate↗
PubMed1977

Hepatotoxic ANIT.

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1-Naphthylisothiocyanate↗
PubMedDate not supplied

Oxidative conversion by rat liver microsomes of 2-naphthyl isothiocyanate to 2-naphthyl isocyanate, a genotoxicant.

The present study investigated the oxidative metabolism of 2-naphthyl isothiocyanate catalyzed by rat liver microsomes. Incubation of 2-naphthyl isothiocyanate, microsomes, and NADPH yielded either N,N'-di-2-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ureas were formed by the production of 2-naphthyl isocyanate, which reacted with its hydrolysis product, 2-aminonaphthalene, to yield the symmetrical urea or, with 2-aminofluorene, to form the mixed urea. Formation of N,N'-di-2-naphthylthiourea was also observed, since 2-aminonaphthalene reacted with the substrate. Urea formation was dependent on microsomes, NADPH, and O2. Use of microsomes from rats previously treated with Aroclor increased urea formation > or = 10-fold. The enzyme activity was inhibited by alpha-naphthoflavone, flavone, or CO and slightly inhibited by metyrapone, 7-ethoxycoumarin, or SKF-525A. It was not inhibited by methimazole or paraoxon. These data are consistent with a cytochrome P-450-dependent, oxidative desulfuration of the isothiocyanate to yield an isocyanate.

1-Naphthylisothiocyanate↗
PubMedDate not supplied

Ultrastructural studies of hepatocyte cytoskeleton in experimental cholestasis by quick-freezing and deep-etching method.

The ultrastructural association between the cytoskeleton and other organelles was studied by the quick-freezing and deep-etching method in rats treated with alpha-naphthylisothiocyanate (ANIT), or phalloidin, and in rats with obstructive jaundice. Cytoplasmic filaments were classified by measuring their diameters, and actin filaments were identified by specific decoration with myosin subfragment 1 (S1). S1-positive actin filaments and S1-negative intermediate filaments (12-14 nm in diameter) were observed to form a three-dimensional network around bile canaliculi, and were more numerous than in controls, not only in phalloidin-treated rats and rats with obstructive jaundice, but also in ANIT-administered rats. In all cholestatic rats, vesicular structures were also more numerous than in controls in the pericanalicular regions, and were closely associated with the microfilaments and the intermediate filaments. Filaments of a new type were localized between the lamellae of rough-surfaced endoplasmic reticulum and mitochondria, and between the lamellae of Golgi sacs and vesicles. Other thin filaments were also observed within the network of actin filaments. These filaments were 4-6 nm in diameter on replica membranes and were never decorated with S1. They were also directly connected with the canalicular membranes. Cytoskeletal components associated with membrane-bound organelles, including these new filaments, were suggested to be involved in the localization and migration of organelles.

1-Naphthylisothiocyanate↗
PubMed1992

Simplified test for determination of drug-oxidizing capacity in rats with chemical-induced liver injury using caffeine and trimethadione as model drugs.

We examined the possibility of predicting the extent of hepatic drug-oxidizing capacity by determination of caffeine, trimethadione and their metabolites in three groups of rats with chemically induced liver injuries. Trimethadione (4 mg/kg) and caffeine (10 mg/kg) were simultaneously administered as two probe drugs. In rats with chemically induced liver injuries pretreated with carbon tetrachloride (CCl4: 0.25 ml/kg), alpha-naphthylisothiocyanate (ANIT: 40 mg/kg), or D-galactosamine (GalN: 400 mg/kg), the half-life (t1/2) of caffeine and trimethadione was significantly (P less than 0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P less than 0.01), whereas apparent volumes of distribution (Vds) were increased in ANIT and GalN groups. In rats with liver damage the production of three metabolites (theobromine, paraxanthine and theophylline) of caffeine as well as the only metabolite (dimethadione) of trimethadione after oral administration of both drugs were significantly decreased compared to those of controls. In rats with liver injuries, total body clearance of caffeine and trimethadione showed a strong correlations (r = 0.99, P less than 0.01); also total body clearance of caffeine correlated well with the ratio of dimethadione/trimethadione after 1, 2, and 4 hr of trimethadione administration (r = 0.93, P less than 0.01; r = 0.97, P less than 0.01 and r = 0.97, P less than 0.01 respectively). Besides, total body clearance of caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P less than 0.01) with the ratio of theobromine/caffeine, paraxanthine/caffeine and theophylline/caffeine after 1, 2 and 4 hr) of caffeine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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