The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system
6 affiliations
- 1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- 2The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- 3Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- 4Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- 5Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
- 6Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
Abstract
Cationic Amphiphilic Drugs (CADs) severely disrupt lysosomal function, which leads to a cellular pathology in humans characterized by excess phospholipids called phospholipidosis. Through a forward genetic screen and mining of published datasets, we discovered that CADs induce the expression of the CYP-35B family of cytochrome P450s and the PGP-13 p-glycoprotein pump via the nuclear receptors NHR-70 and NHR-107 in the nematode C. elegans. A pgp-13 fluorescent reporter revealed hundreds of human drugs that up-regulate the CAD defense system in vivo. Chemoinformatic analyses indicate that the pgp-13 reporter may be useful in identifying CADs that have pathogenic potential in humans. Mutant analyses coupled to metabolomics and structural modeling show that the CYP-35Bs are necessary and sufficient for CAD metabolism, and that CYP-35B2 D311 is key in mediating electrostatic interactions with the positively charged CADs. We also show that CAD metabolites are effluxed via PGP-13 acting partially redundantly with PGP-14 and that an intact defense system is necessary to resist CAD-induced pathology. Finally, we demonstrate that bacteria that likely cohabitate with C. elegans in nature trigger the CAD defense system, providing a plausible explanation for why a pathway that protects against anthropogenic small molecules exists in nematodes.
Cationic amphiphilic drugs (CADs) can collaterally disrupt lysosomal function, inducing pathologies in humans. This study in C. elegans shows that a xenobiotic module couples CYP-35B–mediated CAD catabolism to efflux, likely serving to detoxify natural products generated by microbes in the soil.
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BibTeX
@article{tokmakjian2026nematode,
title = {{The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system}},
author = {Levon Tokmakjian and Duhyun Han and Kateryna Sihuta and Aanchal Aggarwal and Somayeh Pirhadi and Yao Wang and Andrew R. Burns and Brittany Cooke and Siyue Ren and Marios Gavrielatos and Jiabao Liu and Henry M. Krause and Carolyn L. Cummins and Justin Nodwell and David R. Koes and Peter J. Roy},
journal = {PLOS Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pbio.3004006},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004006},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system
AU - Levon Tokmakjian
AU - Duhyun Han
AU - Kateryna Sihuta
AU - Aanchal Aggarwal
AU - Somayeh Pirhadi
AU - Yao Wang
AU - Andrew R. Burns
AU - Brittany Cooke
AU - Siyue Ren
AU - Marios Gavrielatos
AU - Jiabao Liu
AU - Henry M. Krause
AU - Carolyn L. Cummins
AU - Justin Nodwell
AU - David R. Koes
AU - Peter J. Roy
PY - 2026
DA - 2026/09/21
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004006
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004006
AB - Cationic Amphiphilic Drugs (CADs) severely disrupt lysosomal function, which leads to a cellular pathology in humans characterized by excess phospholipids called phospholipidosis. Through a forward genetic screen and mining of published datasets, we discovered that CADs induce the expression of the CYP-35B family of cytochrome P450s and the PGP-13 p-glycoprotein pump via the nuclear receptors NHR-70 and NHR-107 in the nematode C. elegans. A pgp-13 fluorescent reporter revealed hundreds of human drugs that up-regulate the CAD defense system in vivo. Chemoinformatic analyses indicate that the pgp-13 reporter may be useful in identifying CADs that have pathogenic potential in humans. Mutant analyses coupled to metabolomics and structural modeling show that the CYP-35Bs are necessary and sufficient for CAD metabolism, and that CYP-35B2 D311 is key in mediating electrostatic interactions with the positively charged CADs. We also show that CAD metabolites are effluxed via PGP-13 acting partially redundantly with PGP-14 and that an intact defense system is necessary to resist CAD-induced pathology. Finally, we demonstrate that bacteria that likely cohabitate with C. elegans in nature trigger the CAD defense system, providing a plausible explanation for why a pathway that protects against anthropogenic small molecules exists in nematodes. Cationic amphiphilic drugs (CADs) can collaterally disrupt lysosomal function, inducing pathologies in humans. This study in C. elegans shows that a xenobiotic module couples CYP-35B–mediated CAD catabolism to efflux, likely serving to detoxify natural products generated by microbes in the soil.
SN - 1545-7885
ER -