Measuring and modeling of binary mixture effects of pharmaceuticals and nickel on cell viability/cytotoxicity in the human hepatoma derived cell line HepG2
- Helmholtz Centre for Environmental Research - UFZ, Division Health Science, Permoserstr. 15, 04318 Leipzig (Germany)
- Universitaet Leipzig, Faculty of Medicine, Environmental Medicine and Hygiene, Liebigstr. 27, 04103 Leipzig (Germany)
The interaction of drugs and non-therapeutic xenobiotics constitutes a central role in human health risk assessment. Still, available data are rare. Two different models have been established to predict mixture toxicity from single dose data, namely, the concentration addition (CA) and independent action (IA) model. However, chemicals can also act synergistic or antagonistic or in dose level deviation, or in a dose ratio dependent deviation. In the present study we used the MIXTOX model (EU project ENV4-CT97-0507), which incorporates these algorithms, to assess effects of the binary mixtures in the human hepatoma cell line HepG2. These cells possess a liver-like enzyme pattern and a variety of xenobiotic-metabolizing enzymes (phases I and II). We tested binary mixtures of the metal nickel, the anti-inflammatory drug diclofenac, and the antibiotic agent irgasan and compared the experimental data to the mathematical models. Cell viability was determined by three different methods the MTT-, AlamarBlue (registered) and NRU assay. The compounds were tested separately and in combinations. We could show that the metal nickel is the dominant component in the mixture, affecting an antagonism at low-dose levels and a synergism at high-dose levels in combination with diclofenac or irgasan, when using the NRU and the AlamarBlue assay. The dose-response surface of irgasan and diclofenac indicated a concentration addition. The experimental data could be described by the algorithms with a regression of up to 90%, revealing the HepG2 cell line and the MIXTOX model as valuable tool for risk assessment of binary mixtures for cytotoxic endpoints. However the model failed to predict a specific mode of action, the CYP1A1 enzyme activity.
- OSTI ID:
- 21344936
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 244, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.01.012; PII: S0041-008X(10)00023-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Mitochondrial aquaporin-8 knockdown in human hepatoma HepG2 cells causes ROS-induced mitochondrial depolarization and loss of viability
Sustained induction of cytochrome P4501A1 in human hepatoma cells by co-exposure to benzo[a]pyrene and 7H-dibenzo[c,g]carbazole underlies the synergistic effects on DNA adduct formation
Related Subjects
ALGORITHMS
ANTIBIOTICS
BINARY MIXTURES
BROMIDES
DOSES
DRUGS
ENZYMES
HEPATOMAS
LIVER
MEN
NICKEL
RISK ASSESSMENT
SIMULATION
TOXICITY
ANIMALS
ANTI-INFECTIVE AGENTS
BODY
BROMINE COMPOUNDS
CARCINOMAS
DIGESTIVE SYSTEM
DISEASES
DISPERSIONS
ELEMENTS
GLANDS
HALIDES
HALOGEN COMPOUNDS
MALES
MAMMALS
MAN
MATHEMATICAL LOGIC
METALS
MIXTURES
NEOPLASMS
ORGANIC COMPOUNDS
ORGANS
PRIMATES
PROTEINS
TRANSITION ELEMENTS
VERTEBRATES