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ToxSci Advance Access published online on May 5, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl001
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received March 7, 2006
Accepted April 21, 2006

Environmental Toxicology

Cytochrome P450 1A4 and 1A5 in Common Cormorant (Phalacrocorax carbo): Evolutionary Relationships and Functional Implications Associated with Dioxin and Related Compounds

Akira Kubota 1, Hisato Iwata 1 *, Heather M. H. Goldstone 2, Eun-Young Kim 1, John J. Stegeman 3, and Shinsuke Tanabe 1

1 Center for Marine Environmental Studies (CMES), Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
2 Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, MA 02543, USA
3 Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, USA

* To whom correspondence should be addressed.
Hisato Iwata, E-mail: iwatah{at}agr.ehime-u.ac.jp


  Abstract

The present study characterized cytochrome P4501A (CYP1A) isoforms from common cormorant (Phalacrocorax carbo) with regard to their evolutionary relationships and their roles in disposition of dioxin and related compounds (DRCs). Two clones isolated from a cormorant liver cDNA library were named CYP1A4 and CYP1A5 on the basis of greatest overall amino acid identity shared with chicken (Gallus gallus) CYP1A4 (78%) and CYP1A5 (78%), respectively. Spatial heterogeneity in phylogenetic signal along the sequences strongly indicated that cormorant CYP1A4 and CYP1A5 have undergone partial inter-paralog gene conversion, similar to chicken and mammalian CYP1As. Phylogenetic analysis of a putatively unconverted region produced a tree topology consistent with orthology of avian CYP1A5s with mammalian CYP1A2s and avian CYP1A4s with mammalian CYP1A1s. Hepatic CYP1A4 and CYP1A5 mRNA levels in wild cormorants from Lake Biwa, Japan were quantified to examine the effects of DRCs on isoform-specific expression, and to evaluate the toxicokinetics of DRCs in which CYP1A expression is involved. Both CYP1A4 and CYP1A5 mRNA levels were positively correlated with total tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) and concentrations of each congener in most cases in the liver, suggesting the induction of both enzymes through a shared transcriptional mechanism. The lack of correlation of 2,3,7,8-tetrachlorodibenzofuran and 3,3',4,4'-tetrachlorobiphenyl (PCB77) to CYP1A gene expression is likely due to the rapid metabolism of these two congeners. Liver-to-muscle concentration ratios for most DRC congeners except PCB77 and mono-ortho coplanar polychlorinated biphenyls significantly increased with an elevation of CYP1A4 and CYP1A5 mRNA levels. The present data suggest that hepatic sequestration of some DRCs occurs in cormorant via binding to either CYP1A5 or both CYP1A4 and CYP1A5.

Keywords: CYP1A4; CYP1A5; Gene conversion; Dioxin and related compounds; Metabolism; Hepatic sequestration.
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