Phloretin cytoprotection and toxicity

Brian C. Geohagen, Boris Korsharskyy, Amaresh Vydyanatha, Larsulrik R. Nordstroem, Richard M. LoPachin

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Phloretin (Phl) is a dihydrochalcone flavonoid with significant cytoprotective properties; e.g., free radical trapping, electrophile scavenging. Based on this, it has been suggested that Phl might be useful in the treatment of pathogenic processes and prevention of drug toxicities. Therefore, we determined the ability of Phl to provide route- and dose-dependent hepatoprotection in a mouse model of acetaminophen (APAP) overdose. Intraperitoneal (i.p.) administration of Phl produced a bimodal effect; i.e., the highest dose (2.40 mmol/kg) did not prevent APAP-induced lethality, whereas lower doses (0.2–0.4 mmol/kg) afforded modest hepatoprotection. When given alone, the highest i.p. Phl dose was lethal within 24 h, whereas the lower doses were not toxic. Oral Phl (0.40–2.40 mmol/kg) did not prevent APAP-induced hepatotoxicity. The highest oral dose given alone (2.4 mmol/kg) produced 64% lethality, whereas lower doses were not lethal. This toxicity profile was reflected in a study using APAP-exposed isolated mouse hepatocytes, which showed that the Phl pharmacophores, 1,3,5-trihydroxyacetophenone (PG) and 2′,4′,6′-trihydroxyacetophenone (THA) where protective. Corroborative cell free studies showed that polyphenol protectants prevented glutathione loss mediated by the APAP metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Thus, in spite of possessing cytoprotective attributes, Phl was generally toxic in our APAP models. These and earlier findings suggest that Phl is not a candidate for drug design. In contrast, we have found that the enol-forming pharmacophores, THA and PG, are potential platforms for pharmacotherapeutic development.

Original languageEnglish (US)
Pages (from-to)117-123
Number of pages7
JournalChemico-Biological Interactions
Volume296
DOIs
StatePublished - Dec 25 2018

Fingerprint

Phloretin
Cytoprotection
Toxicity
Acetaminophen
Poisons
Imines
Drug Design
Scavenging
Polyphenols
Metabolites
Drug-Related Side Effects and Adverse Reactions
Flavonoids
Pharmaceutical Preparations
Free Radicals
Glutathione
Hepatocytes

Keywords

  • Acetaminophen overdose
  • Drug-induced toxicity
  • Enol-based cytoprotectants
  • Hepatoprotection
  • Phytopolyphenol

ASJC Scopus subject areas

  • Toxicology

Cite this

Phloretin cytoprotection and toxicity. / Geohagen, Brian C.; Korsharskyy, Boris; Vydyanatha, Amaresh; Nordstroem, Larsulrik R.; LoPachin, Richard M.

In: Chemico-Biological Interactions, Vol. 296, 25.12.2018, p. 117-123.

Research output: Contribution to journalArticle

Geohagen, Brian C. ; Korsharskyy, Boris ; Vydyanatha, Amaresh ; Nordstroem, Larsulrik R. ; LoPachin, Richard M. / Phloretin cytoprotection and toxicity. In: Chemico-Biological Interactions. 2018 ; Vol. 296. pp. 117-123.
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