Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase.

We have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin,2 an extremely toxic contaminant formed during the commercial synthesis of the herbicide 2,4,5-trichlorophenoxyacetic acid, is the most potent inducer of aryl hydrocarbon hydroxylase and cytochrome

A Poland; E Glover; A S Kende

2021

Scholarcy highlights

  • From the Department of Pharmacology and Toxicology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
  • We previously hypothesized that the genetic trait of aromatic hydrocarbon nonresponsiveness) is due to mutation which results in an induction receptor with a diminished affinity for the inducing compound
  • We previously postulated that the genetic trait of nonresponsiveness’ in certain inbred strains of mice is due to a mutation which results in the production of an altered induction receptor with a diminished affinity for inducing compounds
  • The experiments presented in this report suggest the following. The cytosol fraction from the liver of C57BL/6J mice contains a small pool of high affinity stereospecific binding sites which reversibly bind
  • (b) This TCDD-binding species has the in uitro binding properties predicted for the hypothesized receptor for induction of aryl hydrocarbon hydroxylase activity-namely, the K. of TCDD-binding approximates the ED, for induction of hepatic hydroxylase activity-and the binding affinities of congeners of TCDD correspond to their potencies as inducers of enzyme activity. The genetic trait of nonresponsiveness is due to a mutation which results in a receptor with diminished affinity for inducing compounds
  • The compound was over 99% pure by gas chromatographic analysis
  • Despite the strength of the correlation between irz vitro and in viva experiments, one should exert caution in equating the hepatic cytosol-binding species with the induction receptor, until it can be shown that the combination of ligand and binding species can evoke a response the induction of hydroxylase activity
  • Hepatic hydroxylase activity in the rat , and a similar potency ratio was found in the C57BL/6J mouse and chick embryo.’ Niwa et al reported that 3-methylcholanthrene was gsO to Moo as potent as TCDD in fetal cell cultures from chick, hamster, rat, rabbit, and responsive strains of mice

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