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Vol. 56, Issue 3, 588-597, September 1999
Biology Department, Woods Hole Oceanographic Institution, Woods
Hole, Massachusetts
Microsomal cytochrome P-450 1A (CYP1A) in a vertebrate model
(the teleost fish scup) is inactivated by the aryl hydrocarbon receptor
agonist 3,3',4,4'-tetrachlorobiphenyl (TCB). Here, the mechanism of
CYP1A inactivation and its relationship to reactive oxygen species
(ROS) formation were examined by using liver microsomes from scup and
rat and expressed human CYP1As. In vitro inactivation of scup CYP1A
activity 7-ethoxyresorufin O-deethylation by TCB was
time dependent, NADPH dependent, oxygen dependent, and irreversible. TCB increased microsomal NADPH oxidation rates, and CYP1A inactivation was lessened by adding cytochrome c. CYP1A inactivation
was accompanied by loss of spectral P-450, a variable loss of
heme and a variable appearance of P-420. Rates of scup liver microsomal
metabolism of TCB were < 0.5 pmol/min/mg, 25-fold less than the
rate of P-450 loss. Non-heme iron chelators, antioxidant enzymes, and
ROS scavengers had no influence on inactivation. Inactivation was
accelerated by H2O2 and azide but not by
hydroxylamine or aminotriazole. TCB also inactivated rat liver
microsomal CYP1A, apparently CYP1A1. Adding TCB to scup or rat liver
microsomes containing induced levels of CYP1A, but not control
microsomes, stimulated formation of ROS; formation rates correlated
with native CYP1A1 content. TCB stimulated ROS formation by
baculovirus-expressed human CYP1A1 but not CYP1A2. The results indicate
that TCB uncouples the catalytic cycle of CYP1A, ostensibly CYP1A1,
resulting in formation of ROS within the active site. These ROS may
inactivate CYP1A or escape from the enzyme. ROS formed by CYP1A1 may
contribute to the toxicity of planar halogenated aromatic hydrocarbons.
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