Model Organisms in Drug Discovery

FISH AS A MODEL ORGANISM 205
genes will be orthologs of mammalian genes whose function in development,
cell signaling or organ physiology has been conserved evolutionarily
(Postlethwait et al., 1998).
A number of laboratories have utilized the zebrafish as a model to study
human diseases (Barut and Zon, 2000; Amatruda et al., 2002; Ward and
Lieschke, 2002). Recent work from several zebrafish laboratories has
identified important aspects of vertebrate physiology that are shared between
zebrafish and mammals. Examples include the biosynthetic pathways of iron
absorption and heme metabolism, which are essential to red blood cell
production (Donovan et al., 2000), and the biology of contractile proteins that
regulate the function of cardiac and skeletal muscle (Sehnert et al., 2002).
Genetic analyses of neural and behavioral physiology, angiogenesis and
cancer biology have been initiated using zebrafish and it is anticipated that
genes discovered in these and other novel mutagenesis screens will identify
genes that play a role in a diverse group of human diseases.
Although relatively few studies devoted specifically to the analysis of
zebrafish physiology have been reported in the past, related teleosts (such as
the carp) and other fish have served for many years as valuable models for the
analysis of mammalian organ function. Most recently, direct analyses of
zebrafish physiology have been performed using pharmacological agents.
These compounds, whose mechanisms of action in humans are well
characterized, show striking conservation of established effects on vascular
tone, behavior, thyroid metabolism and blood coagulation. For example,
vasoconstrictors active in humans, such as phenylephrin and N(G)-nitro-Larginine
methyl ester (L-NAME), cause a reduction of vascular flow through
selected arterial beds of zebrafish larvae (Fritsche et al., 2000; Schwerte and
Pelster, 2000). Similarly, sodium nitroprusside, a vasodilator used to treat
severe hypertension, causes arterial and venous dilatation in zebrafish larvae,
as is observed in humans (Fritsche et al., 2000). Studies also have
demonstrated that diazepam, pentobarbitol and melatonin can induce a
hypnotic-like state in zebrafish, akin to their effects in mammals (Zhdanova
et al., 2001). Importantly, co-administration of specific pharmacological
inhibitors for these compounds prevents their effect with zebrafish. Finally
warfarin, a well-known anticoagulant, exhibits similar effects in zebrafish, and
amiodarone, an important cardiac drug that can inhibit thyroid hormone
metabolism in humans, causes hypothyroidism when administered to
zebrafish larvae (Jagadeeswaran and Sheehan, 1999; Liu and Chan, 2002).
Recently, we have begun genetic analyses of dietary lipid metabolism and
lipid signaling mediators (prostanoids) using the zebrafish. These studies were
born, in part, from our observation that zebrafish larvae digest and process
cholesterol and phospholipids in a manner that is highly analogous to humans
and other mammals. Subsequently, we showed that drugs used to inhibit
cholesterol metabolism in humans have related effects in zebrafish.