Received for publication November 16, 2006.
Revised February 26, 2007.
Accepted for publication February 27, 2007.

Induction of Cyp1a1 is a Non-Specific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants In Vivo and In Vitro

Abstract

Expression of Cyp1a1 and its related enzyme activity have long been used as a biomarker for aryl hydrocarbon receptor (AhR) activation and a warning of dioxin-like toxicity. As a result, induction of Cyp1a1 by pharmaceutical drug candidates or environmental contaminants raises significant concern in risk assessment. The current study evaluates the specificity of Cyp1a1 induction as a marker for AhR affinity and activation, and provides context to assess the relevancy of AhR activation to risk assessment. In vivo experiments examined the expression of Cyp1a1 and other AhR-regulated genes in liver, kidney and heart in response to 596 compounds. From this dataset, a subset of 147 compounds were then evaluated for their ability to activate or bind to the AhR using a combination of gel shift, reporter gene, and competitive receptor binding assays. While in vivo Cyp1a1 mRNA expression is a sensitive marker for AhR activation, it lacks specificity, as 81 out of 137 (59%) compounds were found to significantly induce Cyp1a1 in vivo but were not verified to bind or activate the AhR in vitro. Combining in vivo and in vitro findings we identified 9 AhR agonists, 6 of which are FDA approved and marketed therapeutics, including leflunomide, flutamide and nimodipine. These drugs do not produce dioxin-like toxicity in rats or in humans. These data demonstrate that induction of Cyp1a1 is a non-specific biomarker of direct AhR affinity and activation, and lend further support to the hypothesis that Cyp1a1 induction and/or AhR activation is not synonymous with dioxin-like toxicity.

Key words: Regulation of gene expression, Cytochrome P450, Quinone oxidoreductase, UDP-glucuronyltransferases, Ah receptor, Toxicant-induced gene express

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