Mode of action of pulegone on the urinary bladder of F344 rats

Mitscheli S. Da rocha, Puttappa R. Dodmane, Lora L Arnold, Karen L. Pennington, Muhammad M. Anwar, Bret R. Adams, Sean V. Taylor, Clint Wermes, Timothy B. Adams, Samuel Monroe Cohen

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Essential oils from mint plants, including peppermint and pennyroyal oils, are used at low levels as flavoring agents in various foods and beverages. Pulegone is a component of these oils. In a 2-year bioassay, oral administration of pulegone slightly increased the urothelial tumor incidence in female rats. We hypothesized that its mode of action (MOA) involved urothelial cytotoxicity and increased cell proliferation, ultimately leading to tumors. Pulegone was administered by gavage at 0, 75, or 150 mg/kg body weight to female rats for 4 and 6 weeks. Fresh void urine and 18-h urine were collected for crystal and metabolite analyses. Urinary bladders were evaluated by light microscopy and scanning electron microscopy (SEM) and bromodeoxyuridine (BrdU) labeling index. Pulegone and its metabolites, piperitenone, piperitone, menthofuran, and menthone, were tested for cytotoxicity in rat (MYP3) and human (1T1) urothelial cells by the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. No abnormal urinary crystals were observed by light microscopy. Urine samples (18-h) showed the presence of pulegone, piperitone, piperitenone, and menthofuran in both treated groups. By SEM, bladders from treated rats showed superficial necrosis and exfoliation. There was a significant increase in the BrdU labeling index in the high-dose group. In vitro studies indicated that pulegone and its metabolites, especially piperitenone, are excreted and concentrated in the urine at cytotoxic levels when pulegone is administered at high doses to female rats. The present study supports the hypothesis that cytotoxicity followed by regenerative cell proliferation is the MOA for pulegone-induced urothelial tumors in female rats.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalToxicological Sciences
Volume128
Issue number1
DOIs
StatePublished - Jul 1 2012

Fingerprint

Inbred F344 Rats
Rats
Urinary Bladder
Cytotoxicity
Metabolites
Urine
Tumors
Cell proliferation
Bromodeoxyuridine
Electron Scanning Microscopy
Labeling
Optical microscopy
Microscopy
Flavoring Agents
Mints
Cell Proliferation
Mentha
Light
Food and Beverages
Neoplasms

Keywords

  • Cell proliferation
  • Cytotoxicity
  • Metabolites
  • Mode of action
  • Pulegone
  • Urinary bladder

ASJC Scopus subject areas

  • Toxicology

Cite this

Da rocha, M. S., Dodmane, P. R., Arnold, L. L., Pennington, K. L., Anwar, M. M., Adams, B. R., ... Cohen, S. M. (2012). Mode of action of pulegone on the urinary bladder of F344 rats. Toxicological Sciences, 128(1), 1-8. https://doi.org/10.1093/toxsci/kfs135

Mode of action of pulegone on the urinary bladder of F344 rats. / Da rocha, Mitscheli S.; Dodmane, Puttappa R.; Arnold, Lora L; Pennington, Karen L.; Anwar, Muhammad M.; Adams, Bret R.; Taylor, Sean V.; Wermes, Clint; Adams, Timothy B.; Cohen, Samuel Monroe.

In: Toxicological Sciences, Vol. 128, No. 1, 01.07.2012, p. 1-8.

Research output: Contribution to journalArticle

Da rocha, MS, Dodmane, PR, Arnold, LL, Pennington, KL, Anwar, MM, Adams, BR, Taylor, SV, Wermes, C, Adams, TB & Cohen, SM 2012, 'Mode of action of pulegone on the urinary bladder of F344 rats', Toxicological Sciences, vol. 128, no. 1, pp. 1-8. https://doi.org/10.1093/toxsci/kfs135
Da rocha MS, Dodmane PR, Arnold LL, Pennington KL, Anwar MM, Adams BR et al. Mode of action of pulegone on the urinary bladder of F344 rats. Toxicological Sciences. 2012 Jul 1;128(1):1-8. https://doi.org/10.1093/toxsci/kfs135
Da rocha, Mitscheli S. ; Dodmane, Puttappa R. ; Arnold, Lora L ; Pennington, Karen L. ; Anwar, Muhammad M. ; Adams, Bret R. ; Taylor, Sean V. ; Wermes, Clint ; Adams, Timothy B. ; Cohen, Samuel Monroe. / Mode of action of pulegone on the urinary bladder of F344 rats. In: Toxicological Sciences. 2012 ; Vol. 128, No. 1. pp. 1-8.
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