A more reliable source of experimental human hepatocytes

This may at first seem to be an esoteric development but scientists at the Oregon Health & Science University have succeeded in propagating human liver cells in severely immunocompromised mice. The full report appears in Nature Biotechnology. The work was done in collaboration with colleagues at Stanford University, the University of Pittsburgh, and Texas Children's Hospital at Baylor.

Human liver cells, or hepatocytes, have become an important part of preclinical drug safety testing since the liver is the primary source of drug metabolizing enzymes. These are generally split into the Phase I heme-containing monooxygenase enzymes, cytochrome P450s (CYPs), and the non-heme flavin monooxygenases (FMOs), as well as the Phase II drug-conjugating enzymes such as UDP-glucuronyltransferases and sulfotransferases, among others. Each of these enzymes can act alone or in concert to terminate drug action or produce active metabolites of the parent drug.

New drugs that inhibit or induce the expression of drug metabolizing enzymes can therefore influence how other drugs are handled by the body. These effects are a primary source of drug-drug interactions. These effects can even occur between drugs and herbal medicines: St. John's wort is a known inducer of CYP3A4 and increases the clearance (or reduces blood levels) of many drugs such as the anticancer drug, irinotecan, and the organ transplant immunosuppressant, cyclosporine.

So, why should we care about a limitless, reproducible source of human hepatocytes?

Well, human hepatocytes are usually derived from post-mortem tissues or tissues made available from surgical resection of the liver.

"There are a number of companies that take these leftover livers, process them and ship the cells to people who need them for testing," [senior author Dr Markus] Grompe said. "You have no control over when you get them, and you have no control over the quality when you get them. Many batches of cells are bad, low quality." And human liver cells from living sources are difficult to expand in laboratory tissue cultures.

Researchers are at the mercy of the timing of tissue availability and have no control over the age, drug history, smoking history, etc. of the donor (all factors that can influence basal drug metabolizing enzyme status). Moreover, some of us differ in the genetic status of some of our drug metabolizing enzymes such that researchers don't know if a hepatocyte culture is an "outlier" until they do more complex genetic analyses.

The OHSU group has spun off a company, Yecuris, to commercialize this this more reliable source of a key biological research reagent. Beyond drug metabolism research, human hepatocytes can also be used to study liver-based diseases such as hepatitis C and malaria, as well as basic toxicity testing for drugs and their metabolites.

In fact, basic liver toxicity testing may be as important as drug-interaction studies: the US FDA states that, "drug-induced liver injury (DILI) is now the leading cause of acute liver failure (ALF), exceeding all other causes combined." A 2001 FDA report also notes that drug-induced liver injury is also a leading cause of drug development failure, drug withdrawals, or drug distribution restrictions.

Of course, cultured human hepatocytes may be of limited use in detecting rare, or idiosyncratic, cases of liver damage. Moreover, cultured human hepatocytes are often lacking in cells with immune function (such as Kupffer cells) whose effects may contribute to liver damage.

Nevertheless, this Nature Biotechnology paper on the successful propagation of human hepatocytes in immunocompromised mice represents a major advance in the field.