Examining the evidence of non-monotonic dose-response in androgen receptor agonism high-throughput screening assay.

Examining the evidence of non-monotonic dose-response in androgen receptor agonism high-throughput screening assay. Toxicol Appl Pharmacol. 2020 Nov 17;:115338 Authors: Klimenko K Abstract Modern high-throughput screening (HTS) techniques allow to determine in vitro bioactivity of tens of thousands of chemicals within a relatively short period of time and tested compounds are usually interpreted as either active or inactive. The interpretation is mostly based on the assumption of monotonic dose-response. This approach ignores potential abnormal dose-response relationships, such as non-monotonic dose-response (NMDR). NMDR presents a serious challenge to toxicologists and pharmacologists, since they undermine the usefulness of such concepts as lowest-observed-adverse-effect level (LOAEL) and no-observed-adverse-effect level (NOAEL). The possible presence of the NMDR in androgen receptor (AR) agonism was examined for a structurally diverse set of chemicals (∼8300 unique compounds) from Tox21 project library. The source of activity data is Tox21 AR agonism luciferase-based HTS on the MDA-MB-453 cell line. The examination of curve fitting for 35,328 dose-response data entries was based on modified version of existing criteria for determination of NMDR. The bias that arises from compounds' cytotoxicity and interference with firefly luciferase protein was also studied. The examination has shown evidence of NMDR for several compounds, incl...
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Tags: Toxicol Appl Pharmacol Source Type: research