Comparison of the novel HK-2 human renal proximal tubular cell line with the standard LLC-PK1 cell line in studying drug-induced nephrotoxicity
Established cell lines are widely used as in vitro models in toxicology studies. The choice of an appropriate cell line is critical when performing studies to elucidate drug-induced toxicity in humans. The porcine renal proximal tubular cell line LLC-PK1 is routinely used to study the nephrotoxic ef...
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| Published in | Canadian journal of physiology and pharmacology Vol. 88; no. 4; pp. 448 - 455 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Plattsburgh, NY
National Research Council of Canada
01.04.2010
NRC Research Press Canadian Science Publishing NRC Research Press |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Established cell lines are widely used as in vitro models in toxicology studies. The choice of an appropriate cell line is critical when performing studies to elucidate drug-induced toxicity in humans. The porcine renal proximal tubular cell line LLC-PK1 is routinely used to study the nephrotoxic effects of drugs in humans. However, there are significant interspecies differences in drug pharmacokinetics and pharmacodynamics. The objective of this study was to determine whether the human renal proximal tubular cell line HK-2 is an acceptable model to use when performing in vitro toxicity studies to predict effects in humans. We examined 2 nephrotoxic agents, ifosfamide (IFO) and acyclovir, that exhibit different clinical nephrotoxic patterns. HK-2 cells metabolized IFO to its nephrotoxic metabolite, chloroacetaldehyde (CAA). Acyclovir induced a concentration-dependent decrease in HK-2 cell viability, suggesting that acyclovir may induce direct insult to renal proximal tubular cells. The results support clinical pathology data in humans and suggest that HK-2 cells are a suitable model to use in in vitro toxicity studies to determine drug-induced nephrotoxicity in humans. |
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| AbstractList | Established cell lines are widely used as in vitro models in toxicology studies. The choice of an appropriate cell line is critical when performing studies to elucidate drug-induced toxicity in humans. The porcine renal proximal tubular cell line LLC-PK1 is routinely used to study the nephrotoxic effects of drugs in humans. However, there are significant interspecies differences in drug pharmacokinetics and pharmacodynamics. The objective of this study was to determine whether the human renal proximal tubular cell line HK-2 is an acceptable model to use when performing in vitro toxicity studies to predict effects in humans. We examined 2 nephrotoxic agents, ifosfamide (IFO) and acyclovir, that exhibit different clinical nephrotoxic patterns. HK-2 cells metabolized IFO to its nephrotoxic metabolite, chloroacetaldehyde (CAA). Acyclovir induced a concentration-dependent decrease in HK-2 cell viability, suggesting that acyclovir may induce direct insult to renal proximal tubular cells. The results support clinical pathology data in humans and suggest that HK-2 cells are a suitable model to use in in vitro toxicity studies to determine drug-induced nephrotoxicity in humans. Established cell lines are widely used as in vitro models in toxicology studies. The choice of an appropriate cell line is critical when performing studies to elucidate drug-induced toxicity in humans. The porcine renal proximal tubular cell line LLC-PK1 is routinely used to study the nephrotoxic effects of drugs in humans. However, there are significant interspecies differences in drug pharmacokinetics and pharmacodynamics. The objective of this study was to determine whether the human renal proximal tubular cell line HK-2 is an acceptable model to use when performing in vitro toxicity studies to predict effects in humans. We examined 2 nephrotoxic agents, ifosfamide (IFO) and acyclovir, that exhibit different clinical nephrotoxic patterns. HK-2 cells metabolized IFO to its nephrotoxic metabolite, chloroacetaldehyde (CAA). Acyclovir induced a concentration-dependent decrease in HK-2 cell viability, suggesting that acyclovir may induce direct insult to renal proximal tubular cells. The results support clinical pathology data in humans and suggest that HK-2 cells are a suitable model to use in in vitro toxicity studies to determine drug-induced nephrotoxicity in humans. Key words: HK-2, LLC-PK1, nephrotoxicity, renal, in vitro. Les lignees de cellules etablies sont abondamment utiliseees comme modeles in vitro dans les etudes de toxicologie. Le choix d'une ligneee cellulaire approprieee est important pour comprendre la toxicite des medicaments chez les humains. La ligneee tubulaire proximale renale porcine LLC-PK1 est couramment utiliseee pour examiner les effets nephrotoxiques des medicaments chez les humains. Toutefois, il existe des differences inter-especes significatives dans la pharmacocinetique et la pharmacodynamique des medicaments. La presente etude a eu pour objectif de determiner si la lignee de cellules tubulaires proximales renales humaines HK-2 est un modele qui peut etre utilise; dans les etudes in vitro pour predire les effets toxiques chez les humains. On a examinee deux agents nephrotoxiques, ifosfamide (IFO) et acyclovir, qui preesentent des profils nephrotoxiques cliniques differents. Les reesultats montrent que les cellules HK-2 possedent la machinerie metabolique necessaire pour meetaboliser l'IFO en son metabolite nephrotoxique chloroaceetaldeehyde (CAA). L'acyclovir a entraine une diminution dependante de la concentration de la viabilite; des cellules HK-2, ce qui permet de supposer que l'acyclovir pourrait induire une agression directe aux cellules tubulaires proximales reenales, et conforte les donnees pathologiques cliniques chez les humains. Les reesultats donnent a penser que les cellules HK-2 constituent un bon modele a utiliser dans les etudes de toxicitee in vitro pour determiner la neephrotoxicitee induite par les medicaments chez les humains. Mots-cles: HK-2, LLC-PK1, neephrotoxicitee,reenal, in vivo. [Traduit par la Redaction] Established cell lines are widely used as in vitro models in toxicology studies. The choice of an appropriate cell line is critical when performing studies to elucidate drug-induced toxicity in humans. The porcine renal proximal tubular cell line LLC-PK1 is routinely used to study the nephrotoxic effects of drugs in humans. However, there are significant interspecies differences in drug pharmacokinetics and pharmacodynamics. The objective of this study was to determine whether the human renal proximal tubular cell line HK-2 is an acceptable model to use when performing in vitro toxicity studies to predict effects in humans. We examined 2 nephrotoxic agents, ifosfamide (IFO) and acyclovir, that exhibit different clinical nephrotoxic patterns. HK-2 cells metabolized IFO to its nephrotoxic metabolite, chloroacetaldehyde (CAA). Acyclovir induced a concentration-dependent decrease in HK-2 cell viability, suggesting that acyclovir may induce direct insult to renal proximal tubular cells. The results support clinical pathology data in humans and suggest that HK-2 cells are a suitable model to use in in vitro toxicity studies to determine drug-induced nephrotoxicity in humans.Original Abstract: Les lignees de cellules etablies sont abondamment utilisees comme modeles in vitro dans les etudes de toxicologie. Le choix d'une lignee cellulaire appropriee est important pour comprendre la toxicite des medicaments chez les humains. La lignee tubulaire proximale renale porcine LLC-PK1 est couramment utilisee pour examiner les effets nephrotoxiques des medicaments chez les humains. Toutefois, il existe des differences inter-especes significatives dans la pharmacocinetique et la pharmacodynamique des medicaments. La presente etude a eu pour objectif de determiner si la lignee de cellules tubulaires proximales renales humaines HK-2 est un modele qui peut etre utilise dans les etudes in vitro pour predire les effets toxiques chez les humains. On a examine deux agents nephrotoxiques, ifosfamide (IFO) et acyclovir, qui presentent des profils nephrotoxiques cliniques differents. Les resultats montrent que les cellules HK-2 possedent la machinerie metabolique necessaire pour metaboliser l'IFO en son metabolite nephrotoxique chloroacetaldehyde (CAA). L'acyclovir a entraine une diminution dependante de la concentration de la viabilite des cellules HK-2, ce qui permet de supposer que l'acyclovir pourrait induire une agression directe aux cellules tubulaires proximales renales, et conforte les donnees pathologiques cliniques chez les humains. Les resultats donnent a penser que les cellules HK-2 constituent un bon modele a utiliser dans les etudes de toxicite in vitro pour determiner la nephrotoxicite induite par les medicaments chez les humains. |
| Abstract_FL | Les lignées de cellules établies sont abondamment utilisées comme modèles in vitro dans les études de toxicologie. Le choix d'une lignée cellulaire appropriée est important pour comprendre la toxicité des médicaments chez les humains. La lignée tubulaire proximale rénale porcine LLC-PK1 est couramment utilisée pour examiner les effets néphrotoxiques des médicaments chez les humains. Toutefois, il existe des différences inter-espèces significatives dans la pharmacocinétique et la pharmacodynamique des médicaments. La présente étude a eu pour objectif de déterminer si la lignée de cellules tubulaires proximales rénales humaines HK-2 est un modèle qui peut être utilisé dans les études in vitro pour prédire les effets toxiques chez les humains. On a examiné deux agents néphrotoxiques, ifosfamide (IFO) et acyclovir, qui présentent des profils néphrotoxiques cliniques différents. Les résultats montrent que les cellules HK-2 possèdent la machinerie métabolique nécessaire pour métaboliser l'IFO en son métabolite néphrotoxique chloroacétaldéhyde (CAA). L'acyclovir a entraîné une diminution dépendante de la concentration de la viabilité des cellules HK-2, ce qui permet de supposer que l'acyclovir pourrait induire une agression directe aux cellules tubulaires proximales rénales, et conforte les données pathologiques cliniques chez les humains. Les résultats donnent à penser que les cellules HK-2 constituent un bon modèle à utiliser dans les études de toxicité in vitro pour déterminer la néphrotoxicité induite par les médicaments chez les humains. |
| Audience | Academic |
| Author | Ito, Shinya Koren, Gideon Aleksa, Katarina Gunness, Patrina Kosuge, Kazuhiro |
| Author_xml | – sequence: 1 givenname: Patrina surname: Gunness fullname: Gunness, Patrina organization: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada – sequence: 2 givenname: Katarina surname: Aleksa fullname: Aleksa, Katarina organization: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada – sequence: 3 givenname: Kazuhiro surname: Kosuge fullname: Kosuge, Kazuhiro organization: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada – sequence: 4 givenname: Shinya surname: Ito fullname: Ito, Shinya organization: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada – sequence: 5 givenname: Gideon surname: Koren fullname: Koren, Gideon email: gideon.koren@sickkids.ca organization: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada |
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| SubjectTerms | Acyclovir Acyclovir - toxicity Animals Biological and medical sciences Cell Line Cells Comparative studies Cytochrome P-450 CYP3A - genetics Diagnosis Drugs Effects Fundamental and applied biological sciences. Psychology Glutathione - analysis Health aspects HK-2 Humans Ifosfamide - metabolism Ifosfamide - toxicity in vitro In Vitro Techniques in vivo Kidney diseases Kidney Tubules, Proximal - cytology Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - enzymology Kidney Tubules, Proximal - metabolism LLC-PK1 LLC-PK1 Cells Nephrology nephrotoxicity néphrotoxicité Physiological aspects renal rénal Species Specificity Swine Toxicity Tests - methods Toxicology Vertebrates: anatomy and physiology, studies on body, several organs or systems |
| Title | Comparison of the novel HK-2 human renal proximal tubular cell line with the standard LLC-PK1 cell line in studying drug-induced nephrotoxicity |
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