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In vitro cytotoxicity of tetracyclines and aminoglycosides in LLC-PK(1), MDCK and Chang continuous cell lines
J A Bacon1, D A Linseman, T J Raczniak
1Investigative Toxicology, The Upjohn Company, 301 Henrietta Street, Kalamazoo, MI 49001, USA.
Abstract:
The objective of this study was to determine if cell lines isolated from particular organs retain their sensitivity to xenobiotic toxicity in vitro. The toxicity of chlortetracycline, demeclocycline and tetracycline was examined in the proximal kidney (LLC-PK(1)), distal kidney (MDCK) and human liver (Chang) cell lines. The toxicity of amikacin, gentamicin and neomycin was studied in the LLC-PK(1) and MDCK lines. Cytotoxicity was assessed by cytoplasmic LDH leakage. Kidney cells treated with tetracyclines displayed minimal toxic response. The Chang cell line showed greater sensitivity to these compounds and ranked them as follows: demeclocycline > chlortetracycline > tetracycline. The kidney lines produced the rankings as follows: LLC-PK(1): amikacin > neomycin > gentamicin; MDCK: neomycin > amikacin > gentamicin. The results from the tetracyclines are consistent with the expectation that these compounds would not be nephrotoxic in vitro since in vivo investigations suggest hormonal mediation is required, and would be hepatotoxic in vitro because of direct action of these xenobiotics on liver cells in vivo. Similarly, the aminoglycosides were more toxic to the proximal kidney cells than to the distal cells as seen in vivo. These results suggest that continuous cell lines may provide important information in the assessment of xenobiotic cytotoxicity.
Insights
This study found that continuous cell lines can predict xenobiotic toxicity. Kidney cells showed low sensitivity to tetracyclines, while liver cells were more sensitive, aligning with in vivo observations.
Area of Science:
- Pharmacology
- Toxicology
- Cell Biology
Background:
- Assessing xenobiotic toxicity in vitro is crucial for drug development.
- Understanding organ-specific cell line sensitivity to toxicants aids predictive toxicology.
Purpose of the Study:
- To investigate whether organ-specific cell lines retain in vitro sensitivity to xenobiotic toxicity.
- To compare the cytotoxicity of tetracyclines and aminoglycosides in kidney and liver cell lines.
Main Methods:
- Utilized LLC-PK(1) (proximal kidney), MDCK (distal kidney), and Chang (human liver) cell lines.
- Assessed cytotoxicity by measuring cytoplasmic lactate dehydrogenase (LDH) leakage.
- Examined toxicity of chlortetracycline, demeclocycline, tetracycline, amikacin, gentamicin, and neomycin.
Main Results:
- Kidney cell lines (LLC-PK(1), MDCK) showed minimal response to tetracyclines.
- Chang liver cells exhibited higher sensitivity to tetracyclines, with toxicity ranked: demeclocycline > chlortetracycline > tetracycline.
- Aminoglycoside toxicity in kidney cells followed specific rankings: LLC-PK(1) (amikacin > neomycin > gentamicin) and MDCK (neomycin > amikacin > gentamicin).
- Results align with in vivo data, suggesting hormonal mediation for tetracycline nephrotoxicity and direct hepatotoxicity, and proximal tubule sensitivity to aminoglycosides.
Conclusions:
- Continuous cell lines can effectively predict xenobiotic cytotoxicity.
- Organ-specific cell lines provide valuable insights into differential toxic responses.
- In vitro cytotoxicity assessments using cell lines can inform in vivo toxicity predictions.
