In addition to screening for drugs that induce long QT, zebrafish can be used to screen for drug-drug interactions, which are often caused by modulation of cytochrome P450s (Cyps). For example, terfenadine, a drug that induces long QT and is metabolized by cytochrome Cyp3A4 in humans, causes bradycardia in zebrafish. When terfenadine is challenged with other compounds metabolized by Cyp3A4 such as cimetidine, a leftward shift in the EC50 of terfenadine is observed in zebrafish heart rate, suggesting that terfenadine-induced bradycardia may be used as an index for Cyp3A4 activity. Cyp3A4 metabolizes nearly 50% of small molecules and alteration of its activity may lead to toxicity. Therefore an inexpensive, high-throughput in vivo model that screens compounds for sensitivity to Cyp3A4 will be valuable in preclinical drug discovery.
CYTOCHROME P450 3A ACTIVITY