A Novel Cytochrome P450, Zebrafish Cyp26D1, Is Involved in Metabolism of All-trans Retinoic Acid

Gu, X., Xu, F., Song, W., Wang, X., Hu, P., Yang, Y., Gao, X., and Zhao, Q.
Molecular endocrinology (Baltimore, Md.)   20(7): 1661-1672 (Journal)
Registered Authors
Hu, Ping, Song, Wei, Zhao, Qingshun
Zebrafish, Cyp26, P450, retinoid signaling, retinoic acid, somitogenesis
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Cytochrome P-450 Enzyme System/genetics
  • Cytochrome P-450 Enzyme System/isolation & purification
  • Cytochrome P-450 Enzyme System/metabolism*
  • Embryo, Nonmammalian/metabolism
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Retinaldehyde/metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Tissue Distribution/genetics
  • Tretinoin/analogs & derivatives
  • Tretinoin/metabolism*
  • Vitamin A/metabolism
  • Zebrafish Proteins/metabolism*
16455818 Full text @ Mol. Endocrinol.
Retinoid signaling is essential for development of vertebrate embryos, and its action is mainly through retinoic acid (RA) binding to its retinoic acid receptors and retinoid-X receptors, while the critical concentration and localization of RA in embryos are determined by the presence and activity of Raldhs (retinal dehydrogenases, for RA synthesis) and Cyp26s (cytochrome P450 RA, for degradation of RA). Previously we had identified a novel cyp26 gene (cyp26d1) in zebrafish that is expressed in hindbrain during early development (Gu et al., 2005, Gene Expression Patterns, 5:733-739). Employing reverse phase high performance liquid chromatograph analyses, here we show that zebrafish Cyp26D1 expressed in 293T cells could metabolize all-trans RA, 9-cis RA and 13-cis RA, but could not metabolize retinol or retinal. The metabolites of all-trans RA produced by Cyp26D1 were the same as that produced by Cyp26A1, which are mainly 4-OH-RA and 4-oxo-RA. Performing mRNA microinjection into zebrafish embryos, we demonstrated that overexpression of Cyp26D1 in embryos not only caused the distance between rhombomere 5 and the first somite of the injected embryos to be shorter than control embryos, but also resulted in left-right asymmetry of somitogenesis in the injected embryos. These alterations were similar to those caused by the overexpression of cyp26a1 in zebrafish embryos, and to that which resulted from treating embryos with 1 microM 4-diethylamino-benzaldehyde (Raldh inhibitor), implying that cyp26d1 can antagonize RA activity in vivo. Taken together, our in vitro and in vivo results provided direct evidences that zebrafish Cyp26D1 is involved in RA metabolism.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes