Tissue concentrations and induction of a hepatic monooxygenase in male Wistar rats after repeated doses of defined polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDDs and PCDFs) mixtures.
Two groups of male Wistar rats were treated 16 times (every 3rd day) subcutaneously with a defined mixture of polychlorinated dibenzo-p-dioxins (PCDDs) or of polychlorinated dibenzofurans (PCDFs). These mixtures contained no measurable amount of 2,3,7,8-TCDD. Each single dose was calculated to contain either 57 ng I-TEq (international 2,3,7,8-T4CDD toxicity equivalencies)/kg body weight of the PCDD mixture or 39 ng I-TEq/kg body weight of the PCDF mixture. Both mixtures contained a large excess of non-2,3,7,8-substituted congeners. The activities of ethoxyresorufin O-deethylase (EROD) in liver microsomes were correlated with the corresponding concentrations of PCDDs or PCDFs in hepatic tissue. Data were compared with results obtained after single injections of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-T4CDD). As expected, a complex kinetic situation resulted, because of the different tissue distributions and elimination half-lives of the various congeners: (1) 2,3,7,8-substituted PCDDs: the time course of the concentrations in liver and adipose tissue was similar for all congeners, the levels increased during the treatment period and decreased after treatment. Tissue concentrations of all 2,3,7,8-substituted PCDDs were considerably higher in liver than in adipose tissue. The liver/adipose tissue concentration ratios increased with the degree of chlorination. The ratio of 1,2,3,7,8-P5CDD was much lower than those of all other 2,3,7,8-substituted congeners. (2) 2,3,7,8-substituted PCDFs: 1,2,3,7,8-P5CDF was rapidly eliminated from liver and adipose tissue while 2,3,4,7,8-P5CDF largely persisted after the treatment period in both tissues. 2,3,7,8-T4CDF was eliminated even more rapidly than 1,2,3,7,8-P5CDF and could not be detected after treatment in both tissues. Time courses of the concentrations of 2,3,4,7,8-P5CDF, H6CDFs, H7CDFs and OCDF in liver and adipose tissue were similar: the levels of all congeners increased during the treatment period but no clear-cut decrease was observed within 34 days after the last treatment. Tissue concentrations of all 2,3,7,8-substituted PCDFs were higher in liver than in adipose tissue. The liver/adipose tissue concentration ratios increased with the degree of chlorination. The ratios of 2,3,7,8-T4CDF and 1,2,3,7,8-P5CDF were much lower than those of all other 2,3,7,8-substituted congeners. (3) non-2,3,7,8-substituted PCDDs and PCDFs: a number of non-2,3,7,8-substituted PCDD and PCDF congeners were found in both tissues in concentrations below 1 ng/g. In adipose tissue nearly all congeners were found during the treatment period showing a decrease after the treatment. In liver samples, many higher chlorinated PCDF congeners (with >4 chlorine atoms) could be detected. Most of those substituted in three of the four 2, 3, 7 and 8-positions persisted after treatment. In contrast, only one 1,4,6,9-substituted isomer of each PCDD homologue group was found during treatment with high recoveries after the third injection, but a rapid decline occurred already during the treatment period. (4) EROD activity: a good linear relationship (when using a double-log plot) between the EROD activities and the hepatic concentrations (ng I-TEq/g tissue) was found both in the PCDD-treated (r2= 85.8%) and in the PCDF-treated group (r2=87.3%). A similar correlation (r2=95.6%) was observed in rats treated with 2,3,7,8-TCDD alone (concentration range in liver tissue: 0.2 to 9.7 ng/g wet weight). The concentration-response curves for both the PCDD and PCDF mixtures run parallel to the curve for 2,3,7,8-T4CDD. However, the inductive potency of the PCDD or PCDF mixture was approximately 3-fold or 4-fold lower, respectively, compared with the inductive potency of 2,3,7,8-T4CDD. Thus, the I-TE factors overestimated the potency of the mixtures in the concentration range tested and taking EROD induction as an end point.
Körner
Wolfgang
W
Universität Tübingen, Institut für Organische Chemie, Germany. wolfgang.koerner@lfu.bayern.de
Golor
Georg
G
Schulz
Thomas
T
Wiesmüller
Thomas
T
Hagenmaier
Hanspaul
H
Neubert
Diether
D
D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004790:Enzyme Induction; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D001572:Benzofurans; D004338:Drug Combinations; D000072317:Polychlorinated Dibenzodioxins; C023614:dibenzofuran; D019363:Cytochrome P-450 CYP1A1