Involvement of Cytochrome P450 1A in the toxicity of aryl hydrocarbon receptor agonists : alteration arachidonic acid metabolism and production of reactive oxygen species
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https://hdl.handle.net/1912/5152DOI
10.1575/1912/5152Abstract
Two cytochrome P4501A-dependent mechanisms of aryl hydrocarbon receptor
(AhR) agonist toxicity were examined in the marine teleost scup (Stenotomus chrysops),
alteration of arachidonic acid (AA) metabolism and production of reactive oxygen species
(ROS).
In scup hepatic microsomes, cytochrome P450s including CYP1A and CYP2B-like
proteins catalyzed regioselective metabolism of AA to eicosatrienoic and
hydroxyeicosatetraenoic acids. Benzo[a]pyrene (BP) treatment induced liver microsomal
AA metabolism, but that effect varied with season. Endogenous AA epoxides were
recovered from scup liver, heart, and kidney, and their composition in the liver was altered
by treatment with BP or 2,3,7,8-tetrachlorodibenzo-p-dioxin.
In scup and mammals, the formation of ROS was stimulated by binding of
3,3',4,4-tetrachlorobiphenyl (TCB) to CYP1A, apparently CYP1Al. Attack of that ROS
inactivated scup CYP1A. ROS release and inactivation of CYP1A were stimulated only by
substrates of CYP1A that are slowly metabolized. In vivo, 3,3',4,4',5-
pentachlorobiphenyl (PeCB) potently induced CYP1A mRNA, protein and catalytic activity
at low doses (0.01-0.1 mg/kg), suppressed induction of CYP1A protein and catalytic
activity at a high dose (1 mg/kg) and transiently induced oxidative stress in scup liver. The
suppression of CYP1A induction was organ-dependent, with hepatic CYP1A being most
susceptible to inactivation. The results suggest that ROS could be involved in the in vivo
suppression of scup liver CYP1A by planar halogenated aromatic hydrocarbons.
The reactive oxygen sensitive transcription factor, nuclear factor-KB (NF-KB), was
characterized in scup. An NF-KB consensus binding sequence bound specifically to 3
proteins in scup liver, heart and kidney. One protein was recognized by an antibody to
mammalian p50. Injection alone appeared to activate NF-KB. BP did not increase the
activation ofNF-KB, and PeCB activated NF-KB in only 1 of 2 experiments.
Last, CYP1A induction in endothelial cells of the American eel (Anguilla rostrata), a
site which may be particularly susceptible to alterations in AA metabolism and ROS
production, was described. Eel liver CYP1A responded to BP, 13-naphthoflavone and
TCB in a dose-dependent fashion, and induction was correlated with hepatic inducer
concentration. Endothelial CYP1A was inducible in a number of organs and was
metabolically active. In the rete mirabile, penetration of endothelial CYP1A induction
increased with increasing dose of AhR agonists, corresponding with an increase in inducer
concentration. A transition from endothelial to epithelial staining occurred in the gill, heart
and kidney at high inducer doses.
Description
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution August 1998
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Suggested Citation
Thesis: Schlezinger, Jennifer J., "Involvement of Cytochrome P450 1A in the toxicity of aryl hydrocarbon receptor agonists : alteration arachidonic acid metabolism and production of reactive oxygen species", 1998-08, DOI:10.1575/1912/5152, https://hdl.handle.net/1912/5152Related items
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