A. Poland, E. Glover
Nov 1, 1973
Citations
3
Influential Citations
214
Citations
Quality indicators
Journal
Molecular pharmacology
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin, an extremely potent toxin and teratogen formed during the commercial synthesis of the herbicide 2,4,5-trichlorophenoxyacetic acid, is a potent inducer of δ-aminolevulinic acid synthetase and aryl hydrocarbon hydroxylase in chick embryo liver. The induction of hydroxylase activity is more sensitive to low doses of the toxin than is the induction of δ-aminolevulinic acid synthetase; 2-fold induction is produced by 1.55 pmoles/egg (0.5 ng), and maximal induction by 155 pmoles/egg. Coordinate expression of the two enzymes is also dissociable by the administration of cycloheximide, which selectively inhibits induction of the synthetase. Fifteen halogenated dibenzo-p-dioxins were screened for their ability to induce the two enzymes, and a well-defined structure-activity relationship emerged; all the congeners that induced both enzymes had halogen atoms at a minimum of three of the four lateral ring positions and contained at least one nonhalogenated ring position. There is a perfect correspondence between the whole animal toxicity data on the dibenzo-p-dioxin congeners and their ability to induce both enzymes.