Kinetics and inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) in rats.
The kinetic properties and the inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) were studied in Wistar rats following subcutaneous (s.c.) injections. For assessing the dose-response, rats were treated with a single dose of 3. 10 or 30 microg H7CDD/kg body wt. Tissue concentrations and enzyme induction were measured 1, 2, and 3 weeks after treatment, and in the 30 microg/kg group additionally after 6, 20 and 57 weeks. Tissue concentrations increased dose-dependently from 3 to 30 microg/kg. Concentrations in liver were always higher than in adipose tissue, the concentration ratio: liver/adipose tissue varied between 32 and 67. The activity of (ethoxyresorufin O-deethylase) (EROD) in liver microsomes was clearly induced by H7CDD, reaching maximal induction three weeks after treatment. (3-fold at 3 microg/kg, 5-fold at 10 microg/kg and nearly 30-fold at 30 microg/kg). For assessing the time dependency, tissue levels and hepatic enzyme induction were monitored over a period of 57 weeks after a single s.c.-injection of 30 microg H7CDD/kg body wt. Hepatic concentrations of the congener remained rather constant from the 2nd to the 20th week after treatment (280 ng/g and 319 ng/g, respectively). In contrast, concentrations in adipose tissue and thymus increased 2-fold during this period, and 20 weeks after injection reached a maximum of 11 ng/g and 3 ng/g, respectively. Thereafter, the concentrations decreased and tissue levels of 91 ng/g (liver), 3 ng/g (adipose tissue) and 2 ng/g (thymus) were detected 57 weeks after treatment. The elimination half-life (t 1/2) calculated from our data was 140 days in liver and 130 days in adipose tissue. The reasonable explanation for the increase in tissue concentrations of H7CDD up to 20 weeks after treatment is the slow release of this congener from the subcutaneous injection site. Induction of hepatic EROD activity always closely followed changes in the hepatic concentrations of H7CDD, reaching a maximum 3 weeks after treatment and remaining at this level until the 20th week. Correlation analysis of hepatic H7CDD concentrations versus the extent of EROD induction indicated a linear relationship in a double-logarithmic plot. When compared with TCDD, the hepatic monooxygenase-inducing potency of H7CDD within the low dose range was found in the rat to be 170 to 440-times lower than that of TCDD. Measurement of 14C-caffeine demethylation, using a 14CO2 breath test, revealed a similar time course in vivo when compared with the microsomal EROD activity ex vivo.
Golor
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Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Free University Berlin, Germany.
Yamashita
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Köner
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Hagenmaier
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Neubert
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D000818:Animals; D001944:Breath Tests; D002110:Caffeine / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D006207:Half-Life; D008657:Metabolic Clearance Rate; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution
D000072317:Polychlorinated Dibenzodioxins; D002110:Caffeine; D019363:Cytochrome P-450 CYP1A1; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin