Relationship Between Structure of Phenothiazines and in Vitro Cytotoxicity

Zimmerman, Hyman J.; Kendler, J.

doi:10.3181/00379727-135-35019

Cited by 14 publications

(6 citation statements)

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“…DUJOVNE & ZIMMERMA" (1968) reported that CPZ caused leakage of enzymes from cells in suspension. Similar effects were observed by ZIMMERMAN & KENDLER (1970) when Chang human liver cells were exposed to CPZ or to other phenothiazine derivatives. They assumed that these drugs produced damage to the cells or altered the permeability of their membranes.…”

Section: Resultssupporting

confidence: 70%

The Toxicity of Chlorpromazine and Mescaline on Mouse Cerebellum and Fibroblast Cells in Culture*

Roubein

Samuelly

Keup

1973

Acta Pharmacologica et Toxicologica

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Section: Resultssupporting

confidence: 70%

The Toxicity of Chlorpromazine and Mescaline on Mouse Cerebellum and Fibroblast Cells in Culture*

Roubein

Samuelly

Keup

1973

Acta Pharmacologica et Toxicologica

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“…The low prevalence of gold salt-induced cholestasis, and its possible association with eosinophilia or exfoliative der matitis might suggest an immunoallergic mecha nism. In recent years, the concept has been developed that in order for a drug to trigger an immune response against the liver, the drug may first have some direct hepatotoxicity (11,16,18,19). In rabbits, administration of gold salts induced congestion of the hepatic sinusoids, centrilobular necrosis, and mild steatosis (1).…”

Section: Commentsmentioning

confidence: 99%

Gold Salt-Induced Cholestasis

Pessayre¹,

Feldmann²,

Degott³

et al. 1979

Digestion

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“…These observations are consistent with those obtained with an in vitro system employing Chang cells (4) and rabbit liver slices (1), in which the adverse effects of phenothiazine were enhanced by a trifluomethyl or chlorine atom at the R2 position of the molecule. Attempts have been made in vitro to correlate the known "surface activity" of phenothiazines to their clinical ("tranquilizing") potential (9) ; and a presumed relationship between molecular structure of these compounds and their ability to alter cellular membrane permeability has been inferred (4). Our data indicate that the four phenothiazines tested (CPZ, TFPZ, TFPE and PZ) also interfere with the excretory ability of the ex vivo perfused rat liver either by an effect similar to that on membranes of isolated cells or by some other interference with bile secretion.…”

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confidence: 99%

“…Promazine (PZ), which in contrast to CPZ rarely produces hepatic injury in man ( 3 ) , led to no effect (1) or to a lesser effect ( 2 ) . A further study (4), using suspensions of cells from tissue culture, compared the relative cytotoxicity of several phenothiazine compounds. A trifluoromethyl (-CF3) group, and to a lesser degree a chloride (-C1) substituent in position R2 appeared to increase the %ytotoxic" potential of the phenothiazine compounds.…”

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confidence: 99%

Perfusion of the Isolated Rat Liver with Phenothiazines

Tóth¹,

Kendler²,

Nagpaul³

et al. 1972

Experimental Biology and Medicine

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Previous studies have demonstrated that exposure of rabbit liver slices (1) and of suspensions of "liver" cells (Chang) grown in tissue culture (2) to CPZ leads to leakage of enzymes into the medium. Promazine (PZ), which in contrast to CPZ rarely produces hepatic injury in man ( 3 ) , led to no effect (1) or to a lesser effect ( 2 ) . A further study (4), using suspensions of cells from tissue culture, compared the relative cytotoxicity of several phenothiazine compounds. A trifluoromethyl (-CF3) group, and to a lesser degree a chloride (-C1) substituent in position R2 appeared to increase the %ytotoxic" potential of the phenothiazine compounds. These findings parallel adverse effects of phenothiazines in other in vitro models (inhibition of motility of protozoa (5) , hemolysis Studies on the perfused rat liver in this laboratory (7) have demonstrated that CPZ leads to a decrease in bile flow, hepatic perfusion flow, and in biliary excretion of sulphobromophthalein (BSP) . In the present study the ex vivo perfused rat liver was utilized to compare effects of several phenothiazines on perfusate flow, bile production, and removal and excretion of BSP.Materials and Methods. Preparations. Unfasted female rats ( Sprague-Dawley) weighing 250-350 g were prepared for ex vivo perfusion of their livers as described previously ( 7 ) . The medium for perfusion was a cellfree solution of Krebs buffer (pH 7.4) freshly prepared before each experiment. Sufficient bovine albumin (3 5 % solution, Pentex Biochem.) was added to make a 2.5% concentration, In addition: the perfusate contained 240 mg/100 ml of glucose and 3000 units of heparin (Liquaemin, Organon). (6). Drugs. Promazine (PZ) , triflupromazine (TFPZ) and trifluoperazine (TRPE) were supplied by Smith, Kline and French Laboratories. The drugs were each dissolved in 1.0 ml of saline and added to the perfusate to provide concentrations of 1.0 X 2.5 X loF4 and 5.0 x lo4 mole/liter, respectively.They were added after a period of system equilibration that lasted for 30 min. Tn control experiments 1.0 ml of saline was added instead of the drugs. Measurements of rates of bile and perfusate flows were taken during the subsequent 30 min, after which sulphobromophthalein (BSP) , in a concentration of 10 mg/100 ml of perfusate was added; and the determinations were continued for an additional 45 min. Samples (0.2 ml) of perfusate were drawn at intervals for the determination of BSP removal by the liver. Bile samples (20 pl) containing excreted BSP were collected at intervals for the assay of biliary BSP content, as previously reported ( 7 ) -The rate from a total of 51 perfusions were analyzed for variance of parameters. Student's t was used to test statistical significance of differences between means (8).Results. All three drugs, at concentrations used, decreased BSP removal from the perfusate significantly. At the lowest concentration(1 x M ) , PZ interfered less than did the other two, and the rate of removal of BSP from perfusate did not differ significantly from that of the c...

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Relationship Between Structure of Phenothiazines and in Vitro Cytotoxicity

Cited by 14 publications

References 0 publications

The Toxicity of Chlorpromazine and Mescaline on Mouse Cerebellum and Fibroblast Cells in Culture*

The Toxicity of Chlorpromazine and Mescaline on Mouse Cerebellum and Fibroblast Cells in Culture*

Gold Salt-Induced Cholestasis

Perfusion of the Isolated Rat Liver with Phenothiazines

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