Persistent effects of a single dose of Aroclor 1254 on cytochromes P450IA1 and IIB1 in mouse lung.
The polychlorinated biphenyl mixture Aroclor 1254 has been shown to elicit prolonged biochemical responses in several rodent species, particularly induction of mixed function oxygenases in hepatic tissue. Lung is also of interest since a single dose of Aroclor 1254 has been demonstrated to have a tumor promoting effect, increasing the numbers of lung tumors in Swiss mice initiated with N-nitrosodimethylamine. To investigate the enzyme induction response in lung, male Swiss mice were given a single 100 or 500 mg/kg dose of Aroclor 1254 and euthanized at time intervals ranging from 48 hr to 30 weeks. Both cytochromes P450IA1 and IIB1 were followed by use of specific enzyme activities and Western immunoblotting. The IA1 isoform, as quantified by ethoxyresorufin-O-deethylase activity and immunoblotting with monoclonal antibody 1-7-1, was significantly elevated for 30 weeks after both doses. In contrast, benzyloxy-resorufin-O-dealkylase activity (P450IIB1 specific), which is constitutively expressed in rodent lung, was unaffected by Aroclor treatment at the lower dose at early time points, but induced twofold at 30 weeks. At the higher dose, however, enzymatic activity was decreased to 50% of control values, an effect which persisted for 4 weeks postexposure. These changes were confirmed by Western immunoblotting utilizing monoclonal antibody 2-66-3. Concomitantly, content of individual PCB congeners in lungs and carcass was quantified by gas chromatography with electron capture detection. One congener, 2,3,3',4,4'-pentachlorobiphenyl, was selectively retained in lung compared to carcass. Lack of correlation between changes in lung content of PCBs and levels of the P450 isoforms suggested interactions between congeners in control of P450 induction and repression. These data confirm a prolonged P450 induction response in nonhepatic tissue following Aroclor exposure, and further suggest a bidirectional role for certain PCB congeners in the regulation of P450IA1 and P450IIB1 expression in lung tissue.
Beebe
L
L
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, Maryland 21702.
Fox
S D
SD
Riggs
C W
CW
Park
S S
SS
Gelboin
H V
HV
Issaq
H J
HJ
Anderson
L M
LM
D000818:Animals; D001140:Aroclors / Q000493:pharmacokinetics / Q000494:pharmacology*; D020111:Chlorodiphenyl (54% Chlorine); D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis*
D001140:Aroclors; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1