Hepatotoxicity Testing in Larval Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 85

Chapter 8

Hepatotoxicity Testing
in Larval Zebrafish

Adrian Hill
Evotec (UK) Ltd, Abingdon, Oxfordshire, UK

8.1 INTRODUCTION: THE LARVAL ZEBRAFISH
MODEL

When zebrafish research was in its infancy, the scientific community initially focused
on genetics and development and soon discovered a high degree of conservation
compared to humans (Postlethwait et al., 2000). During the next few decades, the
number of academic researchers working in this field grew rapidly and the zebrafish
was established as a key model system for the study of disease and toxicology with
mechanisms closely echoing those of mammalian model species (Hill et al., 2005;
Zon and Peterson, 2005; Lieschke and Currie, 2007; Barros et al., 2008; Hill, 2008a).
Today, around 3,500 zebrafish peer-reviewed publications are released each year.
In addition to academic research, the zebrafish has also recently gained attention
from the pharmaceutical sector as a tool for the evaluation of novel drug candidates, in
particular as a way of assessing compounds for toxicity and safety liabilities early in
the drug discovery process. As noted in the previous chapters, the transparent nature of
the larvae and the ability to screen in a microtiter plate format with small amounts
(single milligrams) of compounds, as well as other advantages, make the zebrafish an
ideal model. Most importantly, physiological, morphological, and histological sim-
ilarities to mammals and humans can be observed when zebrafish larvae are treated
with organ-specific toxicants and hepatotoxic compounds are no exception.

8.2 LIVER DEVELOPMENT

Hepatocyte precursors have been identified in zebrafish during mid-somitogenesis;
approximately 16 h post fertilization (hpf) (Korzh et al., 2001). One early marker,