Related Experiment Video

Updated: Jun 12, 2026

High-throughput and Comprehensive Drug Surveillance Using Multisegment Injection-Capillary Electrophoresis-Mass Spectrometry
10:17

High-throughput and Comprehensive Drug Surveillance Using Multisegment Injection-Capillary Electrophoresis-Mass Spectrometry

Published on: April 23, 2019

Species used for drug testing reveal different inhibition susceptibility for 17beta-hydroxysteroid dehydrogenase type

Gabriele Möller1, Bettina Husen, Dorota Kowalik

  • 1Helmholtz Zentrum München, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany.

Plos One
|June 15, 2010
PubMed

Insights

Novel 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1) inhibitors show species-specific efficacy. Rodent models may prematurely discard promising human cancer drugs due to lower sensitivity to inhibition, highlighting the need for cautious cross-species evaluation.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Steroid metabolism inhibitors offer potential for treating steroid-related cancers like breast cancer and endometriosis.
  • Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1) is a key target for such therapies.
  • Developing novel 17beta-HSD 1 inhibitors requires understanding species-specific activity.

Purpose of the Study:

  • To validate novel 15-substituted estrone-based compounds as inhibitors of human 17beta-HSD 1.
  • To assess the specificity of these inhibitors across various 17beta-HSD types and species.
  • To evaluate the reliability of animal models for predicting human drug efficacy.

Main Methods:

  • In vitro enzymatic assays using recombinant human 17beta-HSD types (1, 2, 4, 5, 7) and orthologs from marmoset, pig, mouse, and rat.
  • Quantification of inhibitor preferences between human and animal 17beta-HSD 1 enzymes.
  • Molecular docking experiments to predict inhibitor binding and efficacy.

Main Results:

  • Significant differences in steroid conversion inhibition were observed across all analyzed 17beta-HSDs.
  • Rodent 17beta-HSD 1 enzymes showed markedly lower sensitivity to inhibition compared to human 17beta-HSD 1.
  • The marmoset enzyme exhibited the most similar inhibition pattern to human 17beta-HSD 1.
  • Molecular docking accurately predicted the best performing compound for the human enzyme but failed in species-specific predictions.
  • Preclinical rodent models could incorrectly eliminate potentially effective human drug candidates.

Conclusions:

  • Species-specific differences in 17beta-HSD 1 inhibition are profound and impact drug development.
  • Reliance on rodent models for preclinical screening may lead to the premature termination of promising human therapeutics.
  • Careful evaluation of activity and efficacy in heterologous species systems is crucial for successful drug development.

More Related Videos

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

Related Concept Videos

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
Drug toxicity: Idiosyncratic Reactions01:16

Drug toxicity: Idiosyncratic Reactions

Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Pharmacogenetics of Drug Metabolism: Overview01:27

Pharmacogenetics of Drug Metabolism: Overview

Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
Dose-Response Relationship: Selectivity and Specificity01:25

Dose-Response Relationship: Selectivity and Specificity

Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and β2-adrenergic receptors...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...