Zebrafish have an ethanol-inducible hepatic 4-nitrophenol hydroxylase that is not CYP2E1-like

- Zebrafish are an increasingly popular model for toxicology/pharmacology, but translation requires understanding metabolism.
- CYP2E1 is a critical enzyme in clearance or bioactivation of ethanol and a wide range of other drugs and pollutants.
- CYP2E1 was thought to be conserved only in mammals; however, some studies report that CYP2E1 activity exists in zebrafish.
- Herein, we show that there is a 4-nitrophenol hydroxylase in zebrafish liver that is inducible 1.5- to 2-fold by ethanol.
- However, this activity is not CYP2E1-like based on substrate affinity or sensitivity to a CYP2E1 inhibitor 4-methylpyrazole.

Zebrafish are an attractive model organism for toxicology; however, an important consideration in translating between species is xenobiotic metabolism/bioactivation. CYP2E1 metabolizes small hydrophobic molecules, e.g. ethanol, cigarette smoke, and diesel exhaust components. CYP2E1 is thought to only be conserved in mammals, but recent reports identified homologous zebrafish cytochrome P450s. Herein, ex vivo biochemical measurements show that unlike mammals, zebrafish possess a low-affinity 4-nitrophenol hydroxylase (Km ∼0.6 mM) in hepatic microsomes and mitochondria that is inducible only 1.5- to 2-fold by ethanol and is insensitive to 4-methylpyrazole inhibition. In closing, we suggest creating improved models to study CYP2E1 in zebrafish.

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