Oxidative and conjugative xenobiotic metabolism in zebrafish larvae in vivo.
As zebrafish larvae are being increasingly applied to toxicity testing, there is a need to understand the potential for xenobiotic metabolism by these early life-stage organisms. The expression of genes similar to mammalian cytochromes P450 (CYP) 2B6, CYP3A5, and UDP-glucuronosyl transferase (UGT) 1A1, as well as the zebrafish CYP1A was assessed across embryonic development. Activities toward 7-ethoxyresorufin O-deethylase (EROD assay), 7-ethoxycoumarin O-deethylase (ECOD assay), and octyloxymethylresorufin (OOMR assay) were detected at 96 h postfertilization, as was significant phenolic conjugation in the EROD assay (p < 0.001). The induction of CYP1A, the CYP gene zgc:153269, and UGT1A1 after exposure to Aroclor 1254 (100 microg/L, 24 h) was observed, with significant CYP1A induction (p < 0.01). Aroclor exposure also significantly induced EROD activity (p < 0.005), as did coexposure of alpha-naphthoflavone in a dose-dependent manner (p < 0.05; 5 and 10 microM exposures). Inhibition of CYP activity by SKF525A (5 microM) could not be demonstrated because of significant CYP induction as evidenced by OOMR activity (p < 0.05). This study demonstrates that zebrafish larvae express genes similar to mammalian CYP and UGT isoforms throughout early development and have activities toward model CYP substrates. The modulation of these genes and activities by CYP inducers is also reported. The continued use of these model organisms in toxicity testing is supported by this study.
Jones
Huw S
HS
School of Biosciences, The University of Birmingham, Birmingham, West Midlands, United Kingdom.
Panter
Grace H
GH
Hutchinson
Thomas H
TH
Chipman
J Kevin
JK
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007814:Larva / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*; D015027:Zebrafish / Q000378:metabolism*
D016877:Oxidants; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase