{
  "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.\n\nCationic 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada",
    "The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada",
    "Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada",
    "Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America",
    "Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada",
    "Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
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        0
      ],
      "name": "Levon Tokmakjian"
    },
    {
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        1
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      "name": "Duhyun Han"
    },
    {
      "affs": [
        2
      ],
      "name": "Kateryna Sihuta"
    },
    {
      "affs": [
        3
      ],
      "name": "Aanchal Aggarwal"
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    {
      "affs": [
        4
      ],
      "name": "Somayeh Pirhadi"
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    {
      "affs": [
        5
      ],
      "name": "Yao Wang"
    },
    {
      "name": "Andrew R. Burns"
    },
    {
      "name": "Brittany Cooke"
    },
    {
      "name": "Siyue Ren"
    },
    {
      "name": "Marios Gavrielatos"
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    {
      "name": "Jiabao Liu"
    },
    {
      "name": "Henry M. Krause"
    },
    {
      "name": "Carolyn L. Cummins"
    },
    {
      "name": "Justin Nodwell"
    },
    {
      "name": "David R. Koes"
    },
    {
      "name": "Peter J. Roy"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0ccx5egxnr98h.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pbio.3004006",
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  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
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  "native_subjects": [
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  "pmcid": null,
  "pmid": null,
  "published": "2026-09-21",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/0ccx5egxnr98h.ris",
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    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "10.1371/journal.pbio.3004006",
      "source": "plos",
      "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004006"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:biotechnology",
      "subfield": "systems-synthetic"
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      "field": "medicine",
      "origin": "plos:anatomy",
      "subfield": "physiology"
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  "title": "The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system",
  "title_text": "The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:43Z",
  "url": "https://research.draconitic.com/paper/0ccx5egxnr98h",
  "venue": "PLOS Biology",
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}