Ketamine attenuates cytochrome p450 aromatase gene expression and estradiol-17β levels in zebrafish early life stages

William J. Trickler, Xiaoqing Guo, Elvis Cuevas, Syed F. Ali, Merle G. Paule, Jyotshna Kanungo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Ketamine, a dissociative anesthetic, is a noncompetitive antagonist of N-methyl-D-aspartate-type glutamate receptors. In rodents and non-human primates as well as in zebrafish embryos, ketamine has been shown to be neurotoxic. In cyclic female rats, ketamine has been shown to decrease serum estradiol-17β (E2) levels. E2 plays critical roles in neurodevelopment and neuroprotection. Cytochrome p450 (CYP) aromatase catalyzes E2 synthesis from androgens. Although ketamine down-regulates a number of CYP enzymes in rodents, its effect on the CYP aromatase (CYP19) is not known. Zebrafish have been used as a model system for examining mechanisms underlying drug effects. Here, using wild-type (WT) zebrafish (Danio rerio) embryos, we demonstrate that ketamine significantly reduced E2 levels compared with the control. However, the testosterone level was elevated in ketamine-treated embryos. These results are concordant with data from mammalian studies. Ketamine also attenuated the expression of the ovary form of CYP aromatase (cyp19a1a) at the transcriptional level but not the brain form of aromatase, cyp19a1b. Exogenous E2 potently induced the expression of cyp19a1b and vtg 1, both validated biomarkers of estrogenicity and endocrine disruption, but not cyp19a1a expression. Attenuation of activated ERK/MAPK levels, reportedly responsible for reduced human cyp19 transcription, was also observed in ketamine-treated embryos. These results suggest that reduced E2 levels in ketamine-treated embryos may have resulted from the suppression of cyp19a1a transcription. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Original languageEnglish (US)
Pages (from-to)480-488
Number of pages9
JournalJournal of Applied Toxicology
Volume34
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • CYP aromatase
  • Estradiol-17β
  • Gene expression
  • Ketamine
  • Testosterone
  • Zebrafish

ASJC Scopus subject areas

  • Toxicology

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