Abstract
Endothelium is a common site of cytochrome P450 1A (CYP1A) induction in vertebrates, and endothelial CYP1A could affect the distribution and toxicity of CYP1A substrates. We investigated CYP1A induction in organs rich in endothelium, gill, heart, and a microvascular model, the swimbladder rete mirabile, in the eel. Benzo[a]pyrene (BP) and 3,3′,4,4′-tetrachlorobiphenyl (TCB), radiolabeled and injected intraperitoneally, showed similar distribution in eels, with dose-dependent increases in concentration in heart and rete mirabile. BP [given at 0.1, 1, and 10 mg/kg (0.4, 4, and 40 μmol/kg)], TCB [given at 0.1, 1, and 10 mg/kg (0.3, 3, 30, and 60 μmol/kg)], and β-naphthoflavone (BNF) [given at 0.1, 1, 5, 10, and 100 mg/kg (0.4, 4, 20, 40, and 400 μmol/kg)] induced microsomal CYP1A and ethoxyresorufin O-deethylase in heart and rete mirabile. Immunohistochemical analysis confirmed that induction of CYP1A in heart and rete mirabile occurs in the endothelium. Increasing doses of each compound caused increasing penetration of induction into the vascular bed of the rete, but with BNF and BP induction penetrated further than with TCB. At high doses of BNF there also was induction in epithelial cells adjacent to endothelium in gill and kidney. CYP1A also was induced in heart and rete mirabile of eels from sites heavily contaminated by aryl hydrocarbon receptor (AHR) agonists. The penetration of CYP1A induction into capillaries of the rete mirabile reflects the penetration of the inducer itself, consistent with the idea that endothelial CYP1A can indicate the local distribution of AHR agonists. The microvascular rete mirabile in the eel provides a model system to explore further a hypothesis that endothelial CYP1A participates in removal of some AHR agonists from the circulation and to examine the consequences of CYP1A induction to the vascular system.
Footnotes
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Send reprint requests to: John J. Stegeman, Biology Department, Redfield 342, MS 32, Woods Hole Oceanographic Institution, Woods Hole, MA 02543. E-mail: jstegeman{at}whoi.edu
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This research was supported in part by National Institutes of Health Grant P42-ES07381, by Environmental Protection Agency Grant R823889, by Air Force Office of Scientific Research Grant F40620-94-1039, and by the Lyons Fellowship.
- Abbreviations used are::
- pHAH
- planar halogenated aromatic hydrocarbon
- AHR
- aryl hydrocarbon receptor
- BP
- benzo[a]pyrene
- BNF
- β-naphthoflavone
- CYP
- cytochrome P450
- CYP1A
- cytochrome P450 1A
- CPR
- cytochrome P450 reductase
- PAH
- polynuclear aromatic hydrocarbon
- TCB
- 3,3′,4,4′-tetrachlorobiphenyl
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- TCDF
- 2,3,7,8-tetrachlorodibenzofuran
- PCB
- polychlorinated biphenyl
- mAb
- monoclonal antibody
- EROD
- ethoxyresorufinO-deethylase
- Received November 22, 1999.
- Accepted March 8, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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