Liver Specific Toxicity (LST) Screen
Liver toxicity is a major reason for drug discovery failure and is the number one adverse event leading to FDA regulatory action on drugs, including non-approval, postmarketing warnings added to the label, and withdrawal from the market. Pharmaceutical companies, not surprisingly, rank liver toxicity first in research priorities in adverse drug events.
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The study of potential drug-induced liver toxicity aims to answer the following questions:
• early in discovery, does the new molecule have a risk of liver toxicity?
• once marketed, will there be a risk of idiosyncratic toxicity?
The model is designed to identify liver specific toxicity of the non-metabolized (parent) test article.
Hepatocytes (liver epithelial cells) make up about 80% of the mass of the liver. The primary hepatocyte culture represents a well studied and validated cell model consisting of normal liver parenchymal cells. The culture system that offers the most in vivo-like morphology is when cells are grown between two layers of gelled collagen or a bottom layer of collagen and a top layer of Matrigel, known as “sandwich” culture. The collagen interaction stimulates cells to repolarize and form extensive bile canalicular networks.
Unlike standard monolayer cultures of hepatocytes, the cells in sandwich culture are able to form a functional hepatobiliary system. This enables one to evaluate markers for liver toxicity specific to the bile canalicular membrane. It also allows examination of metabolic stability, activation, inhibition of CYP enzymes, induction of CYP enzymes, and inhibition/down-regulation of BSEP (Bile Salt Export Pump). Drugs that inhibit BSEP/UGT1A1 can lead to cholestatic liver toxicity. General cell health is monitored by evaluating compound effects on the canalicular membrane, BSEP, UGT1A1, steatosis, mitochondrial function and membrane integrity.
Liver Specific Toxicity (LST) Screen Assays may be run on primary rat, dog, monkey, or human hepatocytes in sandwich culture.