Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors

Analysis of their human relevance using the IPCS framework

Christian Strupp, Deborah A. Banas, Samuel Monroe Cohen, Elliot B. Gordon, Martina Jaeger, Klaus Weber

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Species-specific lung tumors in the mouse are induced by a number of chemicals. The underlying cause appears to be a high metabolic activity of mouse lung, due to relatively high abundance of Clara cells in mice compared with humans and the mouse-specific cytochrome P450 isoform 2f2 in the Clara cells. The chemicals are activated to reactive intermediates, leading to local cytotoxicity or mitogenicity resulting in increased cell proliferation and tumors. Rats have lower metabolic activity than mice (already below the threshold needed to cause lung tumors upon lifetime exposure) and activity in humans is lower than in rats. The carcinogenic risk for human lung is low for this mode of action (MOA). Fluensulfone has shown an increased incidence of lung adenomas in mice, but not in rats, at high doses. Fluensulfone is not genotoxic. MOA studies were conducted investigating key events of the postulated MOA. Fluensulfone is extensively metabolized by mouse lung microsomes, whereas no metabolic activity is seen with human lung microsomes. Cyp 2f2 is a major contributor in fluensulfone's metabolism and Cyp 2e1 is not involved. Furthermore, administration of fluensulfone to mice led to an early increase in Clara cell proliferation. The International Programme on Chemical Safety (IPCS) MOA and human relevance framework was used to evaluate the collective data on fluensulfone. We concluded that fluensulfone leads to species-specific mouse lung tumors and that these tumors are likely not relevant to human hazard or risk.

Original languageEnglish (US)
Pages (from-to)284-294
Number of pages11
JournalToxicological Sciences
Volume128
Issue number1
DOIs
StatePublished - Jul 1 2012

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Chemical Safety
Cell proliferation
Metabolism
Tumors
Cell Proliferation
Lung
Neoplasms
Rats
Microsomes
Cytotoxicity
fluensulfone
Cytochrome P-450 Enzyme System
Hazards
Protein Isoforms
Human Activities
Adenoma

Keywords

  • Carcinogenicity
  • Cell proliferation
  • Fluensulfone
  • Human relevance
  • IPCS
  • Lung tumors
  • Mode of action

ASJC Scopus subject areas

  • Toxicology

Cite this

Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors : Analysis of their human relevance using the IPCS framework. / Strupp, Christian; Banas, Deborah A.; Cohen, Samuel Monroe; Gordon, Elliot B.; Jaeger, Martina; Weber, Klaus.

In: Toxicological Sciences, Vol. 128, No. 1, 01.07.2012, p. 284-294.

Research output: Contribution to journalArticle

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