Gender, ethnicity and individual differences in hepatic metabolism have major impact on individual drug response, adverse events and attrition rate during drug development. Therefore, there is an urgent need for reliable test systems based on human cells. Yet, the use of primary human hepatocytes (PHHs) is restricted by limited availability, invasive preparation and short-term stability in culture. All other cellular approaches proposed so far have major disadvantages. We investigated whether peripheral human monocytes after cultivation according to our novel protocol (monocyte-derived hepatocyte-like cells (MH cells)) can serve as an in vitro model for hepatocyte metabolism. Enzyme activities, synthesis parameters (coagulation factor VII and urea) and cytochrome (CY) P450 activities and induction were investigated. Furthermore, MH cells were compared with PHH from the same donor. Using our protocol, we could generate cells that exhibit hepatocyte-like properties: These cells show 71±9% of specific ALT activity, 41±3% of CYP3A4 activity and 65±13% of factor VII secretion when compared with PHHs. Consequently, CYP-mediated acetaminophen toxicity and drug interactions could be shown. Moreover, the investigated parameters were stable in culture over at least 4 weeks. Furthermore, MH cells retain gender-specific and donor-specific CYP activities and toxicity profiles, respectively. MH cells show quantitative and qualitative approximation to human hepatocytes concerning CYP-metabolism and toxicity. Our data support individual prediction of toxicity and CYP metabolism. MH cells are a novel tool to investigate long-term hepatic toxicity, metabolism and drug interactions. The liver is an important site of drug metabolism and hepatocytes are mainly responsible for toxification and detoxification of substances. A huge array of enzymes and transporters allows the hepatocyte to metabolize, conjugate and finally excrete xenobiotics and endobiotics. The first step, also referred to as phase-I metabolism, is performed predominantly by enzymes of the cytochrome P450 (CYP450) enzyme family. The CYPs 1A2, 2A6, 2B6, 2D6, 2E1, 3A4 and 3A5 are found in hepatocytes with great abundance. 1 Most CYP enzymes can be induced, that is, their activity in the hepatocyte is increased to manage greater amounts of xenobiotics. This induction is mediated by receptors, such as the pregnane-X-receptor (PXR), 2 the aryl-hydrocarbon receptor 3 and the constitutive androestendione receptor. 1 Knowing the way a substance is metabolized and how a substance interacts with co-medication is crucial for modern drug design. Therefore, hepatocyte models are urgently needed for drug development, because no other cell possesses a comparable equipment of metabolism pathways. The complexity of this system is augmented by different activities of CYP enzymes dependent on sex, age, ethnicity and individual factors, including co-medication. [4][5][6][7] Pharmacogenomics is a powerful tool to identify different individual metabolism patterns, 8 yet this method only d...
