Effect of polyhexamethylene biguanide on rat liver

Aparajita Chowdhury, Lora L. Arnold, Zemin Wang, Karen L. Pennington, Puttappa Dodmane, Ana Paula Farragut-Cardoso, James E. Klaunig, Daniel Cros, Edmond E. Creppy, Samuel M. Cohen

Research output: Contribution to journalArticle

Abstract

Polyhexamethylene biguanide (PHMB), an amphiphilic polymeric biocide, increased liver tumor incidence in male and female rats at 1000 and 1500 mg/L in drinking water, but not at 500 mg/L in previous studies. In another study, PHMB administered in diet at 4000 mg/kg was negative for hepatocellular tumors. The present studies evaluated bioavailability and distribution of PHMB administered in drinking water and diet and possible modes of action (MOA). PHMB in drinking water was unpalatable during the first 3 days, resulting in markedly decreased food consumption and decreased body weight. Ki-67 labeling index was increased in hepatocytes and endothelial cells dose responsively with PHMB administered in drinking water but not diet. Vitamin E had no effect on this. There was no cytotoxicity by histopathology or serum enzymes, and no increase in cytokines TNFα IL-1α or NF-κB. Focal iron deposition in sinusoidal lining cells was detected. Microarray analyses were non-contributory. No effect on CAR or PPARα activation was detected. 14C-PHMB administered at 500, 1000, or 1500 mg/L in the drinking water or 4000 mg/kg in the diet was nearly completely absorbed and excreted in urine, with some fecal excretion. The hypothesized MOA for liver tumors induced by PHMB in drinking water is: 1) severe dehydration and starvation because of unpalatability, followed by ingestion with rapid absorption and urinary excretion; 2) increased hepatocyte proliferation; and 3) induction of hepatocellular foci and tumors. The PHMB-induced rat hepatocellular tumors are unlikely to pose a human cancer risk. However, the actual MOA has not been determined.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalToxicology Letters
Volume285
DOIs
StatePublished - Mar 15 2018

Keywords

  • CAR activation
  • Dehydration
  • Hepatocellular proliferation
  • Iron deposition
  • Mitogenesis
  • PPARα activation

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'Effect of polyhexamethylene biguanide on rat liver'. Together they form a unique fingerprint.

  • Cite this

    Chowdhury, A., Arnold, L. L., Wang, Z., Pennington, K. L., Dodmane, P., Farragut-Cardoso, A. P., Klaunig, J. E., Cros, D., Creppy, E. E., & Cohen, S. M. (2018). Effect of polyhexamethylene biguanide on rat liver. Toxicology Letters, 285, 94-103. https://doi.org/10.1016/j.toxlet.2017.12.032