Toxicity

Introduction

Hepatotoxicity may be the result of the drug itself or, more frequently, a result of the bioactivation process and the production of reactive metabolites. In consequence, the liver is often the primary site of exposure to these toxins, and hepatic injury occurs quite regularly.

Although many in vitro hepatic screens have been developed to determine whether or not a compound can elicit an acute toxic effect, hepatocytes in culture is, as far as known, the model cell system more comparable to liver since primary cultured hepatocytes retain their characteristics at the morphological as well as at the functional level.

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Rodent and non-rodent hepatocytes are seeded on 96 well/plates. Compounds are individually added to monolayers at 6 increasing concentrations. After an incubation period of 24 h, cell viability under all experimental conditions is assayed by means of colorimetrically or photometrically techniques (i.e., MTT, Neutral Red Uptake (NRU), LDH activity, Alamar Blue, etc) and qRT-PCR analysis of mRNA.

In addition,  any morphological changes of the cultures are documented with photomicrographs for reference.

Data Analysis

Determination of 50% cytotoxic concentration (IC50) is calculated based on the slope and linearity of typical concentration-effect curves. The symmetry of the curve is mathematically estimated from regression analysis of the plot, “percentage of control” versus “log of concentration”. The values for “percentage of control” are derived by converting the absolute values of the measured response to a fraction of the control value, i.e. the measured value of the group with no chemical. Using the control value as the 100% level, all subsequent groups are transformed into relative percentage values. This has the added advantage that different experiments can be compared, even when the absolute values of the control groups are not identical