An in vitro approach to the study of target organ toxicity of drugs and chemicals
In Vitro Cellular & Developmental Biology - PlantPublished 1 September 1985
Daniel Acosta, Elsie M. B. Sorensen, David C. Anuforo, David Mitchell, Kenneth S. Ramos, Kenneth S. Santone
Citations109
SJR quartileQ2
SJR score0.41
SNIP0.64
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
The rationale and approach to the study of target organ toxicology with in vitro cellular systems is described and new techniques by which xenobiotics may be evaluated or identified as potential toxicants to living systems are developed.
Abstract
A major goal of our laboratory has been the development of primary culture systems that retain differentiated functions and responses characteristic of intact tissues in vivo. Specifically, we have developed cellular models of primary cultures of rat heart, liver, and kidney cells to explore the mechanisms by which drugs or chemicals may be toxic to key organs of the body and to develop new techniques by which xenobiotics may be evaluated or identified as potential toxicants to living systems. The purpose of this paper is to describe our rationale and approach to the study of target organ toxicology with in vitro cellular systems.
Keywords
MedicinePharmacology, Toxicology and Pharmaceutics
Food and Cosmetics ToxicologyHepatotoxicity. The adverse effects of drugs and other chemicals on the liver
695 Citations1980
The hepatotoxic effects of oncotherapeutic and immunosuppressive agents miscellaneous drugs and diagnostic chemicals afterthoughts on hepatotoxicity appendices are described.
GastroenterologyHepatotoxicity: The adverse effects of drugs and other chemicals on the liver
646 Citations2000Willis C. Maddrey
The Journal of Cell BiologyBIOGENESIS OF ENDOPLASMIC RETICULUM MEMBRANES
592 Citations1966Gustav Dallner, Philip Siekevitz +1 more
Results strongly suggest that new membrane is synthesized in the rough ER and subsequently transferred to the smooth ER in rat hepatocytes during a period of rapid cell differentiation.
Biochemical and Biophysical Research CommunicationsGeneration of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin
544 Citations1977Joel Goodman, Paul Hochstein
The experiments suggest that the formation of oxygen radicals followed by lipid peroxidation may be the basis for the cardiotoxic effects of these drugs.
CellD-valine as a selective agent for normal human and rodent epithelial cells in culture
390 Citations1975Scott F. Gilbert, Barbara R. Migeon
The ability to select for cells with this enzyme has enabled us to maintain epithelial cell populations free from fibroblast overgrowth and to detect D-amino acid oxidase in tissues where it had not previously been reported-fetal human kidney, lung, and cord.
In Vitro Cellular & Developmental Biology - PlantConditions affecting primary cell cultures of functional adult rat hepatocytes
263 Citations1976Brian A. Laishes, Gary M. Williams
The conditions for obtaining representative, primary adult rat hepatocyte cultures were explored and enzymatic liver perfusion which was nondestructive to hepatocytes, the prevention of aggregation of dissociated cells and the selective attachment of viable cells yielded recovery of 50% of the liver cells.
Biochemical JournalEquilibrium relations between the cytoplasmic adenine nucleotide system and nicotinamide–adenine nucleotide system in rat liver
230 Citations1970Richard L. Veech, Luisa Raijman +1 more
The ratio [ATP]/[ADP][P(i)], as measured by direct determination of the three components in rat liver, was found in various nutritional states to have approximately the same value as the ratio [ADP/[ATP]-(i), which implies that the redox state of the NAD couple in the cytoplasm is linked to, and partially controlled by, the phosphorylationState of the adenine nucleotides.
Methods in Cell ScienceEvaluation of cytotoxicity in cultured cells by enzyme leakage
228 Citations1980David Mitchell, Kenneth S. Santone +1 more
A more sensitive and earlier index of cytotoxicity: leakage of cytoplasmic enzymes from injured cells into the culture medium is described.
The American Journal of MedicineMolecular basis for several drug-induced nephropathies
168 Citations1977Jerry R. Mitchell, Randolph J. McMurtry +2 more
These laboratory results are reviewed in the light of the clinical spectrum of the renal injuries, and possible therapeutic implications of these new findings are briefly discussed.
BMJFatal cholestatic jaundice in elderly patients taking benoxaprofen.
166 Citations1982H. Taggart, Jane Alderdice
In Vitro Cellular & Developmental Biology - PlantConditions affecting primary cell cultures of functional adult rat hepatocytes
151 Citations1976Brian A. Laishes, Gary M. Williams
The results are interpreted to indicate that dexamethasone provided a requirement of the in vitro environment for survival and suggest that elaboration of a complex medium is required to maintain hepatocytes in culture.
Toxicology and Applied PharmacologyRenal function tests as indicators of kidney injury in subacute toxicity studies
143 Citations1981William M. Kluwe
Tests of renal function were conducted on adult, male Fischer 344 rats treated for 15 days with biphenyl, carbon tetrachloride or mercuric chloride finding that in vitro accumulation of organic ions, urinary concentrating ability, and kidney weight were the most sensitive and consistent indicators of nephrotoxicity.
Experimental Cell ResearchComparison of different methods of determining cell viability after exposure to cytotoxic compounds
138 Citations1976B. K. Bhuyan, Barbara E. Loughman +2 more
It was found that the stainability of cells after drug exposure depended on the cell line used and the particular drug used, and cell survival as measured by cloning efficiency did not correlate with survival measured by any of the other methods.
Hospital PracticeThe Renal Circulations
113 Citations1978Barry M. Brenner, Reinier Beeuwkes
Newly elucidated aspects of renal vascular anatomy are mapped out and clearly related to the exchange processes that occur at the capillary level in each part of the nephron to produce the final ureteral urine of the required volume and composition.
The Journal of Infectious DiseasesThe Nephrotoxicity of Cephalosporins: An Overview
108 Citations1978Michael Barza
Although the physician should be aware of the possibility of a potential adverse interaction between these groups of antibiotics, the evidence is not sufficiently conclusive to warrant avoidance of the combination when it appears to be therapeutically useful.
In Vitro Cellular & Developmental Biology - PlantHepatotoxicity studies with primary cultures of rat liver cells
104 Citations1978David C. Anuforo, Daniel Acosta +1 more
Cell culture system has been used to study the cytotoxicity of two hepatotoxic agents, tetracycline and norethindrone, and ASAL was found to be the most sensitive in predicting early cell injury and AP the least sensitive.
Biochemical and Biophysical Research CommunicationsApparent lack of correlation between the loss of cytochrome P-450 in hepatic parenchymal cell culture and the stimulation of haem oxygenase activity
102 Citations1978Alan J. Paine, R.F. Legg
It was shown that high levels of cytochrome P-450 could be maintained in liver cell culture in the face of high haem oxygenase activities.
In Vitro Cellular & Developmental Biology - PlantAdult liver parenchymal cells in primary culture: Characteristics and cell recognition standards
102 Citations1974Robert J. Bonney
The results of this study demonstrate that such a culture can perform many of the specific functions characteristic of the adult liver in vivo, and offers many applications for the study of the regulation of adult liver metabolism.
ToxicologyToxicology investigations with cell culture systems
98 Citations1981Annalaura Stammati, Vittorio Silano +1 more
This review sets out to evaluate the effectiveness of these cell culture systems in assessing the toxic potential of chemicals, and tries to focus attention on the most promising applications of cell cultures in toxicology studies for the near future.
Biochimica et Biophysica Acta (BBA) - EnzymologyDistribution of L- and M-type pyruvate kinase between parenchymal and Kupffer cells of rat liver
94 Citations1972Th.J.C. van Berkel, J.F. Koster +1 more
The results obtained suggest that gluconeogenesis is confined to the parenchymal cells of rat liver, suggesting that Kupffer cells only (probably) contain the M-type pyruvate kinase.
Toxicology and Applied PharmacologyEffects of nicotine on cultured rat heart cells
91 Citations1970Duane G. Wenzel, James W. Wheatley +1 more
Cells beat longer in cultures composed chiefly of M-cells than in unseparated cultures, and differences between the two types of cells, in response to higher concentrations of nicotine, were demonstrated by vacuole formation and nuclear changes.
Toxicology and Applied PharmacologyCytotoxicity of acetaminophen and papaverine in primary cultures of rat hepatocytes
69 Citations1980Daniel Acosta, David C. Anuforo +1 more
The time lag observed in the cytotoxicity of acetaminophen and papaverine may be related to the period required for metabolite(s) accumulation and saturation of detoxifying systems of the cultured liver cells.
AtherosclerosisInjury produced by free fatty acids to lysosomes and mitochondria in cultured heart muscle and endothelial cells
68 Citations1974Daniel Acosta, Duane G. Wenzel
Protection of cultures for 24 hr with 50 μg/ml of hydrocortisone before the FFA at 5 × 10 −5 M provided significant protection only against stearate-induced lysosomal labilization.
Journal of Cellular PhysiologySerum dependent growth of primary cultured differentiated fetal rat hepatocytes in arginine‐deficient medium
66 Citations1973Hyam L. Leffert, D. Paul
Fetal rat hepatocytes in primary monolayer cultures multiply in arginine‐deficient medium and the chromosome number of these cells remains diploid, and the final cell density is proportional to the concentration of dialyzed fetal bovine serum in the medium.
Pharmacology & TherapeuticsMetabolism of insecticides by reductive systems
62 Citations1980E. G. Esaac, Fumio Matsumura
In Vitro Cellular & Developmental Biology - PlantIschemic myocardial injury in cultured heart cells: Leakage of cytoplasmic enzymes from injured cells
60 Citations1978Daniel Acosta, Marianne Puckett +1 more
In Vitro Cellular & Developmental Biology - PlantPrimary monolayer cultures of postnatal rat liver cells with extended differentiated functions
56 Citations1978Daniel Acosta, David C. Anuforo +1 more
The reported results indicate that selective, arginine-deficient medium permits primarily the growth of parenchymal hepatocytes found in neonatal rat liver.
Toxicology and Applied PharmacologyButylate hydroxytoluene pretreatment protects against cytotoxicity and reduces covalent binding of aflatoxin B1 in primary hepatocyte cultures
54 Citations1981Charles B. Salocks, Dennis P. H. Hsieh +1 more
It is suggested that reduction of cytotoxicity by BHT was associated with increased output of nontoxic, water-soluble metabolites and decreased binding of metabolites to macromolecules, and indicates that BHT may protect against the acute toxicity and carcinogenicity of aflatoxin B1 in vivo.
Biochemical and Biophysical Research CommunicationsBromsulfophthalein uptake by isolated liver parenchymal cells
53 Citations1976C.F.A. van Bezooijen, Tsehai A.J. Grell +1 more
The presence of an active carrier system for the uptake of bromsulfophthalein by liver parenchymal cells suggests the specific liver function of removing foreign compounds from the serum is investigated.
ToxicologyThe synthesis of metallothionein and cellular adaptation to metal toxicity in primary rat kidney epithelial cell cultures
52 Citations1980M. George Cherian
The results indicate a direct protective role of intracellular metallothionein in the cellular toxicity of cadmium in epithelial cell monolayer culture.
Environmental Health PerspectivesCultured heart cell reaggregate model for studying cardiac toxicology.
44 Citations1978N. Sperelakis
This review represents a summary of the technique of using cultured heart cells as a model system for studying the physiology, pharmacology, biochemistry and toxicology of myocardial cells.
Journal of Toxicology and Environmental HealthCadmium toxicity in primary cultures of rat hepatocytes
43 Citations1982Kenneth S. Santone, Daniel Acosta +1 more
Findings indicate that measures of metabolic integrity of cultured hepatocytes are more sensitive indices of early cadmium cytotoxicity than are routine, nonspecific measures such as cellular protein content and dye-exclusion viability tests, which detect the later stages of cell injury, i.e., cell death.
Environmental Health PerspectivesDifferential effects of nephrotoxic agents on renal transport and metabolism by use of in vitro techniques.
42 Citations1976G. H. Hirsch
The kidney slice technique has been found to be a sensitive indicator in the assessment of halogenated hydrocarbon-induced nephrotoxicity and differential effects of compounds on in vitro organic acid and base trasport provides information about the transport of these compounds as well as about their neph rotoxicity.
Biochemical PharmacologyLong-term maintenance and induction of cytochrome P-450 in primary cultures of rat hepatocytes
41 Citations1982Kenneth F. Nelson, Daniel Acosta +1 more
Developmental Pharmacology and TherapeuticsComparative Inotropic Response of Newborn and Adult RabbitPapillary Muscles to lsoproterenol and Calcium
38 Citations2019Myung K. Park, Paul H. Sheridan +2 more
Newborn rabbit papillary muscles were not only less sensitive to the inotropic effect of isoproterenol and calcium, but also produced significantly less maximal inotropic tension to these agents in comparison to the adult.
Journal of Toxicology and Environmental HealthEvaluation of the cytotoxicity of tricyclic antidepressants in primary cultures of rat hepatocytes
35 Citations1981David Mitchell, Daniel Acosta
Primary cultures of hepatocytes from postnatal Sprague-Dawley rats were grown in arginine-deficient, ornithine-supplemented medium to inhibit fibroblastic overgrowth and to selectively isolate relatively pure cultures of parenchymal hepatocytes to evaluate the cytotoxicity of certain tricyclic antidepressant drugs.
Journal of Toxicology and Environmental HealthCardiotoxicity of tricyclic antidepressants in primary cultures of rat myocardial cells
34 Citations1984Daniel Acosta, Kenneth S. Ramos
Primary cultures of myocardial cells were used to evaluate the cardiotoxic potential of various tricyclic antidepressants and the rank order of cardiotoxicity was amitriptyline greater than imipramine = desipramines greater than nortriptylines.
ToxicologyCytotoxicity of butylated hydroxytoluene and butylated hydroxyanisole in cultured heart cells
34 Citations1978Steven W. Leslie, Shayne C. Gad +1 more
The results of this study suggest that both BHT and BHA, in relatively large concentrations, produce injury to myocardial cells in culture.
Journal of Molecular and Cellular CardiologyUltrastructure of dissociated adult mammalian myocytes
32 Citations1979Robert D. Moses, Frederick H. Kasten
The ultrastructure of enzymatically isolated adult rat ventricular myocytes was studied by transmission electron microscopy and several possible explanations are put forward to explain the reasons why dissociated adult mammalian myocytes cannot survive for long periods of time in tissue culture.
Biochemical PharmacologyMetabolic activation and cytotoxicity of cyclophosphamide in primary cultures of postnatal rat hepatocytes
31 Citations1981Daniel Acosta, David Mitchell
A model of primary cultures of postnatal rat hepatocytes is developed to characterize the metabolic activation of xenobiotics to toxic intermediates and to study the mechanism(s) by which these chemicals produce cellular injury and it is suggested that this co-culture system can be utilized to evaluate the metabolicactivation of Xenobiotics.
British Journal of Clinical PharmacologyAssessment of nephrotoxicity.
30 Citations1982LF Prescott
Renal histology probably provides the best index of nephrotoxicity, but ethical and other constraints limit the frequent use of renal biopsy, and special tests are often required.
The Annual Review of Pharmacology and ToxicologyIn Vitro Methods of Toxicity Evaluation
30 Citations1978Robert G. Tardiff
In the past decade, in vitro test systems have gained increasing popularity not only because of advantages in mecha nistic investigations but also because of pragmatic considerations such as lower costs and shorter durations of experimentation.
Environmental Health PerspectivesCardiac lesions induced by chemicals.
28 Citations1978Tibor Balázs, V J Ferrans
The pathogenesis, morphological changes and toxicologic features of these cardiomyopathies are described with particular reference to their detection in preclinical toxicity studies.
Archives of ToxicologyPrimary monolayer culture of liver parenchymal cells and kidney cortical tubules as a useful new model for biochemical pharmacology and experimental toxicology
23 Citations1980Peter Bellemann
The induction of slowly inducible foreign compound-metabolizing enzymes by phenobarbital, 3-methylcholanthrene, and dexamethasone were studied in long-term monolayer culture for the investigation of renal enzyme adaptation during progressive time in culture.
In Vitro Cellular & Developmental Biology - PlantIschemic myocardial injury in cultured heart cells: Preliminary observations on morphology and beating activity
23 Citations1977Daniel Acosta, Marianne Puckett
An in vitro model of myocardial ischemia has been established with primary monolayer cultures of neonatal rat heart cells and there was a time-dependent decrease in beating activity as the M cells were exposed to longer durations of ischemic conditions.
Toxicology and Applied PharmacologyCytotoxicity of isoproterenol to cultured heart cells: Effects of antioxidants on modifying membrane damage
23 Citations1983Kenneth S. Ramos, Alan B. Combs +1 more
The data indicate that antioxidants may be useful in reducing injury induced by toxic doses of ISO, and mitochondrial injury may be involved significantly with the development of ISO-induced cardiotoxicity.
ToxicologyCardiotoxicity of diazepam in cultured heart cells
22 Citations1977Daniel Acosta, Richard Chappell
The responses of primary cultures of rat myocardial cells to diazepam (Valium) were evaluated and cytotoxic effects were measured quantitatively by leakage of lactic dehydrogenase from the cells into the media and by cell viability.
Biochemical PharmacologyRole of calcium in isoproterenol cytotoxicity to cultured myocardial cells
22 Citations1984Kenneth S. Ramos, Alan B. Combs +1 more
The results show that agents which modify slow calcium-channel transport do not prevent ISO-induced calcium overload in the cell culture system, and antioxidants may prevent the formation of oxidative metabolites from ISO and the subsequent calcium overload.
ToxicologyInfluence of chronic Cd intoxification on the alkaline phosphatase activity of liver and kidney; biochemical, histochemical and histological investigations
22 Citations1979J. H. J. Copius-Peereboom-Stegeman, J Melet +2 more
The decrease of alkaline phosphatase activity in the kidney should be considered as a real decrease in the amount of this enzyme due to cell degeneration, in combination with the biochemical results.
ToxicologyPreventory by L(−) ascorbic acid of isoproterenol-induced cardiotoxicity in primary cultures of rat myocytes
22 Citations1983Kenneth S. Ramos, Daniel Acosta
Results show that AA protects against the LDH release and decreased cellular viability caused by toxic doses of ISO, and was added to some cultures immediately after exposure to ISO.
The Histochemical JournalA permeability test for the study of mitochondrial injury inin vitro cultured heart muscle and endothelioid cells
20 Citations1975Daniel Acosta, Duane G. Wenzel
Treatment of the cultures with either vitamin A or chlorpromazine, resulted in more rapid mitochondrial staining and brief pre-fixation of the cells with cold acetone also labilized the mitochondria as did a delay in the change of culture medium.
Toxicology and Applied PharmacologyCarbon monoxide and cultured rat heart cells
19 Citations1972George M. Brenner, Duane G. Wenzel
The beating rate of untreated muscle cell cultures declined, presumably due to endothelioid cell overgrowth, and the number of lysosomes in muscle cells was reduced by carbon monoxide, which is proposed as a mechanism for its toxicity.
Experimental and Molecular PathologyThe lead-poisoned cell: A fine structural study using cultured kidney cells
18 Citations1977Judie Walton, Ian K. Buckley
The results suggest that the cell transports lead ions by the same mechanisms that it uses for calcium ion translocation, and that once in the cytoplasm, lead ions are avidly taken up by mitochondria whose functions are thereby seriously impaired.
PubMedEffect of HgCl2 on rat kidney cells in primary culture.
15 Citations1976Hajime Inamoto, Yukiko Ino +3 more
The effect of mercury showed a biphasic pattern both in dose-response and time-response relationships and once the cells were exposed to HgCl2 for a certain period, RNA syntehsis was irreversibly inhibited.
Methods in Cell ScienceMeasurement of functional metabolic activity as a sensitive parameter of cytotoxicity in cultured hepatocytes
11 Citations1982Kenneth S. Santone, Daniel Acosta
Two early, sensitive indices of cytotoxicity involving differentiated liver function are described: maintenance of cellular urea levels and lactate to pyruvate ratio.
Methods in cell biologyChapter 12 The Cultured Heart Cell: Problems and Prospects
11 Citations1980Melvyn Lieberman, William J. Adam +1 more
EnzymeEase of Solubilization of Five Marker Enzymes inThree Preparations of Rat Renal Brush Border Membranes
9 Citations2017Betty Y.L. Hsu, Pamela D. McNamara +4 more
Correlating the degree of solubilization for five marker enzymes with the types of stripping agents used and with the appearance of the membrane surface when examined by electron microscopy led to the suggestion that LAPase, GGTase,GGHase and maltase molecules are part of an interwoven surface layer of membrane proteins which can be disrupted by transamidation and transesterification reactions.
British Journal of PharmacologyINITIAL INVESTIGATIONS INTO ADRENALINE ACCUMULATION AND ADRENERGIC RESPONSIVENESS IN CULTURED NEONATAL RAT HEART CELLS
9 Citations1978M.J.A. Walker
A much smaller accumulation process was observed in fibroblasts which respond to adrenaline with reversible morphological changes, and was not blocked by a variety of uptake blocking agents or α‐ and β‐adrenoceptor antagonists.
Cellular and Molecular Life SciencesIschemic myocardial injury in cultured heart cells: In situ lysosomal damage
9 Citations1978Daniel Acosta, Marianne Puckett +1 more
Primary cultures of rat myocardial cells which were subjected to oxygen and glucose deprivation, 2 conditions associated with ischemia, were evaluated for alterations in lysosomal integrity and changes in latent acid phosphatase activity and lysOSomal membrane permeability.
In Vitro Cellular & Developmental Biology - PlantTemperature and species differences in susceptibility of kidney cell cultures to mercury toxicity
8 Citations1978Herta M. Vickrey, Daisy S. McCann
Toxicology and Applied PharmacologyCarbon monoxide and cultured rat heart cells II. Interaction of carbon monoxide and hypoxia on growth and contractile activity
7 Citations1973Duane G. Wenzel, George M. Brenner
In contrast to the lack of a demonstrable interaction of carbon monoxide and hypoxia on muscle cell beating, a significant additive or potentiative effect on cell growth was obtained with concentrations of 75% carbon Monoxide and either 2.5% or 5% oxygen.
ToxicologyCytotoxicity of caffeine in cultured heart cells
7 Citations1976Daniel Acosta, David C. Anuforo
The cytotoxic effect of caffeine on myocardial cells was evaluated in primary cultures of rat heart muscle (M) and endothelioid (E) cells and Pretreatment with hydrocortisone prior to exposure to caffeine protected E and M cell lysosomes from the labilizing effects of caffeine.
In Vitro Cellular & Developmental Biology - PlantCell injury of cultured rat myocardial cells after reoxygenation of hypoxic cultures in the presence and absence of calcium
7 Citations1984Daniel Acosta, Kenneth S. Ramos +1 more
It is shown that reoxygenation injury is more severe in myocyte cultures previously deprived of both oxygen and calcium than in cultures deprived of oxygen in the presence of calcium.
PubMedCadmium nephropathy.
6 Citations1981W Y Chan, Owen M. Rennert
The involvement of metallothionein in cadmium nephropathy and the nephrotoxic effects of Cadmium-thionein are discussed.
In Vitro Cellular & Developmental Biology - PlantCellular injury of primary cultures of rat myocytes incubated in calcium-free medium followed by recovery in calcium
3 Citations1983Daniel Acosta, Kenneth S. Ramos +1 more
Primary monolayer cultures of rat myocardial cells were used to study the cellular injury that occurs when calcium is reintroduced after a period of calcium depletion and the myoctte calcium content increased progressively with time and cellular injury was manifested by significant leakage of LDH.
Journal of Molecular and Cellular CardiologyAttenuation by antioxidants of Na+/K+ ATPase inhibition by toxic concentrations of isoproterenol in cultured rat myocardial cells
1 Citations1984D ACOSTA, Alan B. Combs +1 more
The present study was designed to determine if isoproterenol, a synthetic catecholamine, inhibits the sodium/potassium ATPase activity in a primary culture system of rat myocardial cells.