Interactions between xenobiotics that increase or decrease the levels of cytochrome P-450 isozymes in rabbit lung and liver.
Isozyme-specific enzymatic activities, radial immunodiffusion, and Western blotting were used to study the effects of phenobarbital, Aroclor 1260, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on microsomal levels of cytochrome P-450 forms 2, 5, and 6. The pulmonary concentration of form 2 was decreased to trace levels by the administration of Aroclor 1260 but not TCDD; co-administration of phenobarbital did not mitigate the decrease. The pulmonary concentration of form 5 was not significantly changed following treatment with Aroclor 1260, phenobarbital, or TCDD. The pulmonary content of form 6 was increased 5- and 10-fold by administration of Aroclor 1260 and TCDD, respectively, and decreased 2-fold by treatment with phenobarbital. Further, phenobarbital antagonized the induction of form 6 by Aroclor 1260 but not by TCDD. In the liver, increases and decreases in form 2-mediated benzphetamine N-demethylation were observed following treatment with Aroclor 1260 depending on the time after dose and individual rabbit response. Hepatic induction of form 2 by phenobarbital was significantly decreased by co-administration of Aroclor 1260. However, form 5 was induced in the liver by either Aroclor 1260 or phenobarbital or both. Thus, the effect of Aroclor 1260 on the control of the concentration of form 2 is independent of that of form 5 in the lung and liver. Fractionation of the Aroclor 1260 to remove co-planar polychlorinated biphenyls and dibenzofurans was useful in demonstrating that the pulmonary induction of form 6 was dependent on these components and unrelated to the repression of form 2 in the lung and liver. The apparent repressive effect of phenobarbital on form 6 in the lung is interesting as it suggests an interaction between phenobarbital and polycyclic hydrocarbon-mediated induction.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000302:isolation & purification; D004147:Dioxins / Q000494:pharmacology*; D004790:Enzyme Induction; D007527:Isoenzymes / Q000235:genetics* / Q000302:isolation & purification; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011817:Rabbits
D001140:Aroclors; D004147:Dioxins; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; C026987:aroclor 1260; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital