Differential enzyme induction of mouse liver and lung following a single low or high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
The induction response of cytochrome P-450-dependent enzyme activities to a single low (5 nmol/kg) or high (50 nmol/kg, intraperitoneal [ip] dose of TCDD was examined in liver and lung homogenates over a 12-week time course in an outbred, Ah-responsive strain of mice (National Institutes of Health [NIH] Swiss). Total hepatic cytochrome P-450 was quantified, and the dealkylation of ethoxy- and benzyloxyresorufin (activities of P-450 IA1 and IIB1, respectively) were measured in both tissues at 48 and 96 hr and at 1, 4, and 12 weeks post-TCDD administration. Western immunoblotting with monoclonal antibody 1-7-1 was conducted to confirm the specific IA1-inductive effects of each dose of TCDD over the same time course. Following the low dose, specific IA1 induction was apparent in liver at the earliest time point, was maximal at 1 week, and declined to control values at 12 weeks. Pulmonary IA1 was near-maximally induced at 48 hr, and remained at that level for 4 weeks. In contrast, a tenfold higher dose of TCDD elicited similar IA1 induction profiles for both tissues, with a maximum at 1 week and a progressive loss at 4 and 12 weeks postexposure. P-450 IIB1 activity was elevated in TCDD-treated animals by enzymatic assay; however, Western immunoblotting did not confirm this finding. These data demonstrate persistent dose-dependent P450 induction over many weeks by a single TCDD dose, with significant organ-specific differences: (a) lung is more sensitive than liver to a nonmaximal inducing dose of TCDD, and (b) at a maximally inducing dose of TCDD, lung is very similar to liver in both the level and time course of IA1 induction.
Beebe
L
L
Laboratory of Comparative Carcinogenesis, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.
Park
S S
SS
Anderson
L M
LM
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006984:Hypertrophy / Q000139:chemically induced; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1