Abstract
A micropillar/microwell chip platform with 3D cultured liver cells has been used for HTP screening of hepatotoxicity of bisphenol A (BPA), an endocrine-disrupting chemical. We previously found the hepatotoxicity of BPA is alleviated by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase 2 (ALDH2). In this study, we have tested potential BPA detoxification with Korean pear (Pyrus pyrifolia) extract, stimulators of ADH and ALDH, as well as arbutin, a reference compound in the pears, on the micropillar/microwell chip platform with human liver cells. Surprisingly, the toxicity of BPA was reduced in the presence of Korean pear extract, indicated by significantly increased IC50 values. The IC50 value of BPA with Korean pear extract tested against HepG2 cells was shifted from 151 to 451 μM, whereas those tested against Hep3B cells was shifted from 110 to 204 μM. Among the tested various concentrations, 1.25, 2.5, and 5 mg/mL of the extract significantly reduced BPA toxicity (Ps < 0.05). However, there was no such detoxification effects with arbutin. This result was supported by changes in protein levels of ADH in the liver cells.
Highlights
For the safety of new drugs and risk assessment of potential environmental toxicants, alternative animal studies have been developed for the purpose of 3R, known as replacement—the substitution of conscious living higher animals for insentient material; reduction—reduction in the number of animals used to obtain information of a given amount and precision; refinement—any decrease in the severity of inhumane procedures applied to those animals [1]
bisphenol A (BPA) and pear extract were toxic to Hep3B and HepG2 cells at the highest concentrations, whereas arbutin was nontoxic at the test concentrations
To evaluate BPA detoxification in the presence of Korean pear extract and arbutin, we considered to use the maximum concentration of 10 mg/mL pear extract and 10 μM arbutin, where the baseline cell viability was greater than 80% at those concentrations (Figure 3)
Summary
For the safety of new drugs and risk assessment of potential environmental toxicants, alternative animal studies have been developed for the purpose of 3R, known as replacement—the substitution of conscious living higher animals for insentient material; reduction—reduction in the number of animals used to obtain information of a given amount and precision; refinement—any decrease in the severity of inhumane procedures applied to those animals [1]. Metabolism-induced toxicity of xenobiotics in the liver has been overlooked, which could be critical to determine potential human toxicity due to the significant discrepancy between animal and human metabolism in the liver. Many toxicologists have been longing for alternative animal platforms that could accurately mimic compound metabolism in the human liver and determine potential augmented toxicity and detoxification of compounds. To this end, our group has been developing 3D cell-based HTS platforms, including micropillar/microwell chips, to determine metabolism-induced toxicity of compounds [5,6,7,8,9,10]
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