Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

Yu Okuda, Masahiko Kushida, Hiroko Kikumoto, Yoshimasa Nakamura, Hashihiro Higuchi, Satoshi Kawamura, Samuel Monroe Cohen, Brian G. Lake, Tomoya Yamada

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 μM) and a major metabolite Z-CMCA (5-1,000 μM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans.

Original languageEnglish (US)
Pages (from-to)773-788
Number of pages16
JournalJournal of Toxicological Sciences
Volume42
Issue number6
DOIs
StatePublished - Dec 1 2017

Fingerprint

Pyrethrins
Rats
Tumors
Hepatocytes
Neoplasms
DNA
Messenger RNA
constitutive androstane receptor
Cytochrome P-450 CYP2B1
Phenobarbital
Metabolites
Liver
Refractory materials
Wistar Rats
Rodentia

Keywords

  • Carcinogenesis
  • Cell proliferation
  • Humanized mice
  • Liver tumor
  • MOA
  • Nongenotoxic

ASJC Scopus subject areas

  • Toxicology

Cite this

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin. / Okuda, Yu; Kushida, Masahiko; Kikumoto, Hiroko; Nakamura, Yoshimasa; Higuchi, Hashihiro; Kawamura, Satoshi; Cohen, Samuel Monroe; Lake, Brian G.; Yamada, Tomoya.

In: Journal of Toxicological Sciences, Vol. 42, No. 6, 01.12.2017, p. 773-788.

Research output: Contribution to journalArticle

Okuda, Yu ; Kushida, Masahiko ; Kikumoto, Hiroko ; Nakamura, Yoshimasa ; Higuchi, Hashihiro ; Kawamura, Satoshi ; Cohen, Samuel Monroe ; Lake, Brian G. ; Yamada, Tomoya. / Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin. In: Journal of Toxicological Sciences. 2017 ; Vol. 42, No. 6. pp. 773-788.
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abstract = "High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 μM) and a major metabolite Z-CMCA (5-1,000 μM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans.",
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AU - Nakamura, Yoshimasa

AU - Higuchi, Hashihiro

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AU - Cohen, Samuel Monroe

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