Subchronic dietary exposure to Aroclor 1254 in rats: accumulation of PCBs in liver, blood, and adipose tissue and its relationship to induction of various hepatic drug-metabolizing enzymes.
Female F344/NCr rats were exposed continuously (7-84 days) or discontinuously (7 days exposure/21 days control diet or 28 days exposure/56 days control diet) to various dietary concentrations (1-100 ppm) of Aroclor 1254. There were dose- and time-dependent increases in PCB levels in liver, blood, and adipose tissue. Following removal of the rats from diet containing Aroclor 1254, there was a relatively rapid decrease in PCB levels, particularly in rats exposed to higher concentrations of Aroclor 1254. In parallel with the alterations in PCB levels observed, the rats showed striking dose- and time-dependent increases in hepatic levels of CYP1A1 and CYP1A2, as determined by various methods [RNA analysis, immunochemical detection, or measurement of the O-dealkylation of methoxyresorufin (CYP1A2) or ethoxyresorufin (CYP1A1)]. In rats removed from the Aroclor 1254 diet, catalytic activity for CYP1A1 as well as RNA levels for both CYP1A1 and CYP1A2 rapidly diminished. In contrast to the high levels of induction of CYP1A1 and CYP1A2 observed, limited induction (< 5-fold) of epoxide hydrolase, quinone oxidoreductase, and aldehyde dehydrogenase was detected, even in rats exposed to the highest concentration of Aroclor (100 ppm) for up to 84 days. Furthermore, induction of these non-CYP hepatic drug-metabolizing genes exhibited distinctly different concentration-response curves. The ratios of hepatic CYP1A1 activity to hepatic PCB burden were similar for rats exposed continuously to Aroclor in the diet for 7, 28, or 84 days, and for rats exposed discontinuously (7 days Aroclor/21 days control diet or 28 days Aroclor/56 days control diet). Thus, hepatic PCB levels alone appeared to be reasonably predictive of CYP1A1 levels under a variety of modes of exposure. When the ratio of CYP1A1 activity to adipose or blood PCB concentration was determined, similar ratios were observed for rats exposed continuously for 7, 28, or 84 days. However, lower ratios were observed for rats discontinuously exposed to Aroclor in the diet. These results have important implications with respect to: (a) employing PCB levels in various tissues to predict biological effects, and (b) determining different concentration-response curves for the various biological effects induced by PCBs.
Dragnev
K H
KH
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, Maryland 21702-1201.
Beebe
L E
LE
Jones
C R
CR
Fox
S D
SD
Thomas
P E
PE
Nims
R W
RW
Lubet
R A
RA
D000273:Adipose Tissue / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000818:Animals; D001140:Aroclors / Q000008:administration & dosage / Q000633:toxicity*; D001483:Base Sequence; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D020111:Chlorodiphenyl (54% Chlorine); D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003640:Dealkylation; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis; D005260:Female; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000096:biosynthesis; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D011078:Polychlorinated Biphenyls / Q000097:blood / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344
D001140:Aroclors; D002273:Carcinogens; D020111:Chlorodiphenyl (54% Chlorine); D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D000444:Aldehyde Dehydrogenase; D010089:Oxidoreductases, N-Demethylating; D004851:Epoxide Hydrolases