Assessment of Drug-Induced Cardiotoxicity in Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 45

Table 4.2 Comparison of Cardiotoxicity in Zebrafish and Humans

Known adverse
cardiotoxic side
effects in humans

Cardiotoxicity
observed in
zebrafish

Abnormal AV
ratio in
zebrafish Drug name

Clozapine Yes Yes Yes

Erythromycin Yes Yes Yes

Quinidine Yes Yes Yes

Terfenadine Yes Yes Yes

Astemizole Yes Yes Yes

Amiodarone Yes Yes Yes

Lidocaine Yes Yes Yes

Verapamil Yes Yes Yes

Haloperidol Yes Yes Yes

Clomipramine Yes Yes No

blood flow, and the heartbeat is associated with pacemaker activity. The underlying
development, patterning, genes, functions, and disease characteristics are similar to
humans, making zebrafish a valuable animal model for studying cardiotoxicity.

4.3 SUMMARY OF CARDIOTOXICITY STUDY DESIGN
AND RESULTS

The goals of this studywere to assess the effects on zebrafish of short-termexposure to
10 cardiotoxic drugs. LC 50 was calculated and then heart rate, rhythmicity, circu-
lation, and morphology were assessed. For heart rate and rhythmicity, 2 day
post fertilization (dpf) zebrafish were exposed to varying concentrations of com-
pounds for 4 h. For morphology assessment, zebrafish were exposed continuously to
compounds for 24 h. Compounds that had significant effects on each of the cardiac-
specific end points were identified (Table 4.1). Results from this study were in good
agreement with results observed in previously published data in zebrafish, other
vertebrate models, and humans (Table 4.2). Together the results reported here
demonstrate that (1) zebrafish exhibit a clear dose response to known cardiotoxic
compounds, and (2) effects of known cardiotoxic drugs in zebrafish are strikingly
similar to effects observed in primates and other preclinical animal models.

4.4 MATERIALS AND METHODS

4.4.1 Experimental Animals

Embryos were generated by natural pairwise mating, as described in The Zebrafish
Book (Westerfield, 1993). Four to five pairs of adult zebrafish were set up for each
mating, and, on average, 100-150 embryos per pair were generated. Embryos were