# Interactions between metabolism, transport, and toxicity of benzalkonium chlorides

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $463,606

## Abstract

Project Summary
 Benzalkonium chlorides (BACs) are widely used antimicrobials in disinfecting products, medical products,
consumer products, and food processing industries, suggesting humans may be exposed chronically and sys-
temically to BACs through a variety of routes. Our preliminary study found that close to 50 of 100 random hu-
man plasma samples contain detectable levels of BACs, suggesting BACs are indeed absorbed. The ongoing
COVID-19 pandemic has led to greatly increased use of BAC-containing disinfectants, which is concerning
given accumulating evidence in respiratory, developmental, reproductive, and neurological toxicities inflicted by
BACs and BAC-induced disruption of cholesterol and lipid homeostasis in rodents. However, there is a lack of
knowledge on the metabolism, transport, and biological consequences of BACs in humans. Our goal is to
characterize the pathways of metabolism and transport of BACs and their impact on nephrotoxicity of BACs.
The potential for nephrotoxicity is supported by previous studies in rats showing that BACs accumulate to the
highest level in the kidney after oral intake and our preliminary studies showing that BACs exert potent cytotox-
icity in a 3D “kidney-on-a-chip” microphysiological system (MPS). Recently, we reported that BACs are metab-
olized by human cytochrome P450 (CYP) isoforms CYP2D6 and CYP4s in vitro. Furthermore, we found that
BACs are actively transported by human organic cation transporters (hOCTs). Because CYP2D6, CYP4s, and
hOCTs are highly polymorphic with greatly varying protein activities, we hypothesize that toxicities of BACs in
kidney are dependent on the activities of BAC-metabolizing and transporting proteins in both liver and kidney.
In Aim 1, we will characterize pathways of metabolism and transport of BACs in vitro, including secondary me-
tabolism by β-oxidation and glucuronidation and transport by hOCTs, human multidrug and toxin extrusion pro-
teins, and P-glycoprotein. In Aim 2, we will evaluate nephrotoxicity induced by BACs in human proximal tubule
epithelial cells in 3D integrated liver-kidney “organs-on-chips” MPS. An integrated sterolomics, lipidomics, and
transcriptomics approach will be used to systemically assess the toxicity and biological activities of BACs. In
Aim 3, we will assess BAC exposure levels and their correlation with lipid and kidney injury biomarkers in hu-
mans, as well as the impact of genetic variations on BAC metabolism and disposition. The significance of this
project lies in that it will, for the first time, address the knowledge gap in metabolism, transport, and toxicity of
BACs in humans. Elucidation of the contribution of reduced activities in CYPs and/or transporters to BAC tox-
icity would enable us to identify high-risk human population with genetic variations in these proteins. The
gained knowledge could also inform federal agencies on setting more appropriate exposure limitations. The
innovation of this project lies in a) a novel ex...

## Key facts

- **NIH application ID:** 10207171
- **Project number:** 1R01ES031927-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Libin Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,606
- **Award type:** 1
- **Project period:** 2021-09-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207171

## Citation

> US National Institutes of Health, RePORTER application 10207171, Interactions between metabolism, transport, and toxicity of benzalkonium chlorides (1R01ES031927-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10207171. Licensed CC0.

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