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Bazzi, Rana and Bradshaw, Tracey D. and Rowlands, J. Craig and Stevens, Malcolm F.G. and Bell, David Robert (2009) 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the Aryl Hydrocarbon Receptor. Toxicology and Applied Pharmacology, 237 (1). pp. 102-110. ISSN 0041-008X

Abstract

2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and related compounds are a series

of anti-cancer candidate pharmaceuticals (Table 1.), that have been shown to activate the

AhR. We show that these compounds are high affinity ligands for the rat AhR, but a quantitative

assay for their ability to induce CYP1A1 RNA in H4IIEC3 cells, a measure of activation of the

AhR, showed a poor relationship between affinity for the AhR and ability to induce CYP1A1

RNA. 5F 203, an agonist with low potency, was able to antagonise the induction of CYP1A1

RNA by TCDD, while IH 445, a potent agonist, did not antagonise the induction of CYP1A1

RNA by TCDD, and Schild analysis confirmed 5F 203 to be a potent antagonist of the induction

of CYP1A1 RNA by TCDD in H4IIEC3 cells. In contrast, several benzothiazoles show potent

induction of CYP1A1 RNA in human MCF-7 cells, and 5F 203 is unable to detectably antagonise

the induction of CYP1A1 RNA in MCF-7 cells, showing a species difference in antagonism.

Evaluation of the antiproliferative activity of benzothiazoles showed that the ability to

agonise the AhR correlated with growth inhibition both in H4IIEC3 cells for a variety of benzothiazoles,

and between H4IIEC3 and MCF-7 cells for 5F 203, suggesting an important role

of agonism of the AhR in the anti-proliferative activity of benzothiazoles.

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