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Toxicology

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Hepatotoxicity

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The liver is a major site of metabolism and elimination of foreign substances, which render the liver a preferred target for drug toxicity. Hepatotoxicity means chemical-driven liver damage. Drugs can cause liver toxicity through couples of mechanisms, such as directly acting or indirectly through reactive metabolites. Moreover, drugs or their metabolites cause hepatotoxicity through specific receptor binding, or lead to direct cytotoxicity by reactive metabolites reacting with hepatic macromolecules. Hepatotoxicity is an important cause of drug development or the withdrawal after marketing. It is reported that a total of 34
drugs were withdrawn from markets between 1995 and 2005, and the main reason for withdrawals was hepatotoxicity.

Available Hepatotoxicity Services

To acquire the acknowledgment of hepatotoxicity in the pre-clinical stage, Creative Animodel offers a wide range of services.
Cytochrome P450 Enzyme Assays
Cytochrome P450 enzymes metabolize a large number of xenobiotics, which may lead to the formation of hepatotoxic compounds. Creative Animodel can offer various and reliable cytochrome P450 enzyme assays for hepatoxicity.
Cellular Drug-Drug Interaction Assays
Drug-drug interaction (DDI) can cause clinical ineffectiveness or adverse drug reaction. Creative Animodel provides a wide range of services to investigate cellular drug-drug interactions.
Membrane Integrity
Measuring cell membrane integrity has been used to evaluate chemical cytotoxicity. After interacting with toxins, mammalian cells experience a series of structural and morphological changes which lead to the lose of membrane integrity. Creative Animodel can evaluate the cell membrane integrity by lactate dehydrogenase (LDH) release or propidium iodide (PI) dye exclusion.
Apoptosis
It is known that the toxic effects including necrosis or apoptosis may occur at higher concentrations of drugs. And apoptosis is a typical pathological feature of liver diseases. Creative Animodel offers professional services about apoptosis.
Mitochondrial Dysfunction
The mitochondria are important for maintaining hepatocyte integrity and functions. Mitochondria dysfunction occurs when the hepatocyte experience excessive physiologic stress. Creative Animodel offers services to detect mitochondrial dysfunction.
Glutathione (GSH) Assay
Glutathione (GSH) is an important antioxidant. GSH depletion is one of the key mechanisms involved in drugs induced hepatotoxicity. Creative Animodel offers GSH assays for testing compounds.
Oxidative DNA Damage
Creative Animodel can conduct assays to detect oxidative DNA damage. Oxidative DNA damage is an inevitable consequence of cellular metabolism with a propensity for increased levels following toxic insult.
3D Hepatotoxicity Screening
Creative Animodel offers hepatotoxicity screening services using 3D cell culture models derived from hepatocytes. 3D cell cultures can resemble the complex in vivo microenvironment to provide reliable data regarding drug safety.

Our AdvantagesVarious hepatocytes available, including primary human hepatocytes, and hepatocytes from non-human species (mouse, rat, dog, etc)Both 2D and 3D hepatotoxicity models availableValidated assays conducted according to regulatory authorities, such as FDA and EMA

With professional experts and state-of-the-art technologies, Creative Animodel offers a wide range of hepatotoxicity services in a cost-efficient and time-saving manner. If you have any questions or specific needs, please feel free to contact us.

References:
1. Cho M. H, et al.; A bioluminescent cytotoxicity assay for assessment of membrane integrity using a proteolytic biomarker. Toxicology in Vitro. 2008, 22(4): 1099-1106.
2. Committee for Medicinal Products for Human Use. Non-clinical guideline on drug-induced hepatotoxicity EMEA. CHMP/SWP/150115/2006. London: European Medicines Agency, 2008.

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