Hepatotoxicity Testing in Larval Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 88

another class C vps gene. In contrast, a third mutant involving the tumor suppressor
gene nf2 manifested extrahepatic choledochal cysts in the common bile duct, similar
to those observed in humans. In addition, in a further study, genes that underlie
Alagille syndrome, a pediatric disorder that results in a variety of abnormalities
including a paucity of intrahepatic bile ducts, play an important role in zebrafish
biliary development (Lorent et al., 2004). These examples therefore illustrate the
utility of zebrafish as a suitable model vertebrate for studying liver development,
disease, and potentially toxic insult.
8.4 HEPATOTOXICITYTESTINGINDRUGDISCOVERY
Regulatory legislation exists to ensure that any new drug administered to patients has
passed a standardized series of toxicity and safety assessments, but those that fail and
are identified late in development using current techniques, due to toxic liabilities, are
very costly to the pharmaceutical industry and would have needlessly been exposed to
numerous test animals during its evaluation. Currently, there is no in vivo or in vitro
model available that can fully assess novel candidate drug compounds for safety and
toxicity liabilities before being progressed into clinical development. In particular, for
certain kinds of organ toxicity such as hepatotoxicity, regulatory animal testing has
shown the poorest correlation with humans (Olson et al., 2000) and as a result is the
most frequent reason cited for labeling drugs with a black box warning and for
withdrawal of approved drugs from the market such as iproniazid and troglitazone
(Fung et al., 2001).
Various different types of hepatic injuries including those caused by alcohol
abuse, infection, and toxic insult all can cause a similar pattern of histological
degeneration and ultimately lead to cirrhosis (Shin and Fishman, 2002). However, the
underlying mechanisms that lead to liver failure are poorly understood.
Liver disease has been on the increase since the 1970s and was responsible for
over 15,000 deaths in 2007 in the UnitedKingdom according to the British Liver Trust
(http://www.britishlivertrust.org.uk) andUKNational Statistics (www.statistics.gov.uk).
In comparison, about 27,500 deaths related to liver disease were recorded for 2005
in the United States (Kung et al., 2008). Whereas choledochal cysts and ARC
syndrome are relatively rare, nearly 1-2% of U.S. citizens have fatty liver disease
and steatosis is found in about a quarter of the U.S. population (Neuschwander-Tetri
and Caldwell, 2003) making it among the most common hepatic pathologies in the
developed world (Clark et al., 2001; Neuschwander-Tetri and Caldwell, 2003). In
addition, due to the association of liver disease with obesity, this number is predicted
to increase further as the number of obese individuals in the United States approaches
one-third of the population (CDC, 2007). Notwithstanding the importance of these
figures, it is also necessary to understand that as people can survive with 70% liver
damage, there is a substantial burden of morbidity from liver disease with the
associated economic costs.
Drug-induced liver injury (DILI) is the most common cause of death from acute
liver failure and accounts for approximately 13% of cases of acute liver failure in the