Membrane effects of various drugs on isolated rat hepatocytes and erythrocytes

Yasuhara, Hajime; Tonooka, Mayumi; Kamei, Katsuhiko; Sakamoto, Koji

doi:10.1016/0041-008x(85)90142-5

Cited by 25 publications

(8 citation statements)

References 19 publications

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“…Hydrophilic bile acids therapy with ursodeoxycholic acid or ursocholic acid failed to inhibit abnormal bile acid synthesis in patients with CTX. In young children, common side effects of CDCA treatment include diarrhea and liver dysfunction [Yasuhara et al, 1985]. Cholic acid supplementation may be an alternative to CDCA for infants and young children with CTX [Setchell and Heubi, 2006].…”

Section: Future Studies In Slosmentioning

confidence: 99%

Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders

Svoboda

Christie

Eroğlu

et al. 2012

American J of Med Genetics Pt C

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Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic condition with a broad phenotype that results from deficiency of the final enzyme of the cholesterol synthesis pathway. This defect causes low or low-normal plasma cholesterol levels and increased 7- and 8-dehydrocholesterol (DHC) levels. Many therapies for SLOS and other disorders of sterol metabolism have been proposed, and a few of them have been undertaken in selected patients, but robust prospective clinical trials with validated outcome measures are lacking. We review the current literature and expert opinion on treatments for SLOS and other selected sterol disorders, including dietary cholesterol therapy, statin treatment, bile acid supplementation, medical therapies and surgical interventions, as well as directions for future therapies and treatment research.

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Section: Future Studies In Slosmentioning

confidence: 99%

Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders

Svoboda

Christie

Eroğlu

et al. 2012

American J of Med Genetics Pt C

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“…An RBC suspension of 4x10' cellls ml-' was prepared as described by Yasuhara et al [40]. An RBC suspension of 4x10' cellls ml-' was prepared as described by Yasuhara et al [40].…”

Section: Cytotoxicity Experimentsmentioning

confidence: 99%

Effect of bilirubin on erythrocyte shape and haemolysis, under hypotonic, aggregating or non-aggregating conditions, and correlation with cell age

Brites

Silva

Brito

1997

Scandinavian Journal of Clinical and Laboratory Investigation

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The effect of unconjugated bilirubin on the morphology and haemolysis of human erythrocytes was accomplished under distinct incubation conditions: (i) hypotonic medium, with bilirubin concentrations ranging from 1 x 10(-9) to 1 x 10(-4) mol l-1; (ii) isotonic medium, with 171 mumol l-1 bilirubin, in the absence of albumin (aggregating conditions), using non-separated and age-fractionated erythrocytes; (iii) isotonic medium, with 171 mumol l-1 bilirubin, in the presence of a surplus of human serum albumin (non-aggregating conditions), and using sulfisoxazole as a bilirubin displacer (bilirubin/albumin and sulfisoxazole/ albumin molar ratios of 0.5 and 4.0, respectively). Our data showed that low concentrations of bilirubin (1 x 10(-7) to 1 x 10(-5) mol l-1) protect against hypotonic haemolysis and induce crenation, while higher bilirubin concentrations induce haemolysis and lead to membrane disruption. When aggregating conditions were used, these phenomena were reproduced, the younger cells being significantly more susceptible to crenation while the older erythrocytes showed increased susceptibility to haemolysis. In non-aggregating conditions, haemolysis was virtually absent, though crenation was evident. Based on the above observations we conclude that the first step of erythrocyte bilirubin toxicity is crenation due to an expansion of the outer membrane leaflet by bilirubin mono-anion location. This effect is more evident in younger cells and explains the protection against the hypotonic haemolysis. Insertion of bilirubin deeper into the bilayer, facilitated by higher concentrations (> or = 1 x 10(-4) mol l-1) and cell age, produces an unstable situation, where bilirubin acid aggregation is apparently the main cause for haemolysis and cell destruction.

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“…It has been demonstrated that chemically unrelated amphiphiles can affect several membraneassociated functions by intercalation of the molecules into the lipid bilayer leading to alterations in membrane dynamics (Isomaa et al, 1986). Membrane effects of amphiphilic drugs on erythrocytes proved to be useful for in vitro hepatotoxicity screening, because drugs which have a membrane-stabilizing effect in red cells at low concentrations and hemolytic effects at higher concentrations were shown to induce enzyme leakage from hepatocytes (Yasuhara et al, 1985). In accordance with this, the results from our studies with red cells indicate that there is a positive correlation between the ability of drugs to induce LDH leakage in hepatocytes and their hemolytic potential in red cells (except IMP).…”

Section: Evaluation and Sensitivity Of The In Vitromentioning

confidence: 99%

“…In particular, the cytotoxic effects of neuroleptics and tricyclic antidepressants have been tested using isolated rat hepatocyte suspensions (Abernathy et al, 1975(Abernathy et al, , 1977Salhab et al, 1979;Tsao et al, 1982;Goethals et al, 1984;Yasuhara et al, 1985) or monolayer cultures of rat hepatocytes (Mitchell and Acosta, 1981;Jung et al, 1985). Enzyme leakage was most often chosen as the endpoint for toxicity.…”

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confidence: 99%

Relative cytotoxicity of psychotropic drugs in cultured rat hepatocytes

Boelsterli¹,

Bouis²,

Donatsch³

1987

Cell Biol Toxicol

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The relative cytotoxic effects of ten psychotropic drugs were assessed in rat hepatocyte monolayer cultures. Clear concentration-related toxicity was seen in the narrow range of 10(-5) M to 5 X 10(-5) M. The four cytotoxicity endpoints chosen were: release of the cytosolic enzyme, lactate dehydrogenase, and impairment of biosynthesis and secretion of proteins, bile acids and glycerolipids. LDH leakage and inhibition of protein secretion into the culture medium proved to be the parameters which allowed the best differentiation between the test compounds. The inhibition of glycerolipid secretion was the most sensitive test in relation to concentration and time of exposure. Based on the effects of these endpoints, the following ranking of relative in vitro toxicity, using equimolar drug concentrations, could be established: clomipramine greater than imipramine = thioridazine greater than chlorpromazine greater than amitriptyline = fluperlapine greater than haloperidol greater than promazine greater than clozapine much greater than sulpiride. This ranking order of in vitro cytotoxicity correlated well with the potential of the drugs to impair liver function in man. Only clozapine had to be classified as a false negative. There was, however, no correlation between the cytotoxicity and the intracellular accumulation of the test drugs. Furthermore, the comparison of the data obtained with psychotropics with the data from five other amphiphilic cationic drugs was consistent with the widely accepted concept of a direct toxic interaction of the drugs with cytomembranes. This nonspecific toxicity of the membrane-active drugs was further corroborated by a positive correlation between their potential to induce LDH leakage in hepatocytes and their ability to induce hemolysis in red cells. In conclusion, the results obtained in our study strongly suggest that it is possible to assess the relative cytotoxicity of psychotropic drugs in rat hepatocyte cultures. It is proposed that this in vitro system provides a useful tool to evaluate new drugs at an early stage of their development, and to identify the most promising candidates within a class of structurally related compounds. In addition, it allows information to be obtained on possible mechanisms of cytotoxicity.

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Membrane effects of various drugs on isolated rat hepatocytes and erythrocytes

Cited by 25 publications

References 19 publications

Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders

Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders

Effect of bilirubin on erythrocyte shape and haemolysis, under hypotonic, aggregating or non-aggregating conditions, and correlation with cell age

Relative cytotoxicity of psychotropic drugs in cultured rat hepatocytes

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