Enolate-forming phloretin pharmacophores: Hepatoprotection in an experimental model of drug-induced toxicity

Brian C. Geohagen, Amaresh Vydyanathan, Boleslav Kosharskyy, Naum Shaparin, Terrence Gavin, Richard M. LoPachin

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2′,4′,6′-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.

Original languageEnglish (US)
Pages (from-to)476-486
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume357
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

Phloretin
Acetaminophen
Drug-Related Side Effects and Adverse Reactions
Phloroglucinol
Theoretical Models
Imines
Acetylcysteine
Hepatocytes
Cytoprotection
Mitochondrial Membranes
Intraperitoneal Injections
Free Radicals
Oral Administration
Cell Survival
Oxidative Stress
Metals
Pharmacology
Ions

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Enolate-forming phloretin pharmacophores : Hepatoprotection in an experimental model of drug-induced toxicity. / Geohagen, Brian C.; Vydyanathan, Amaresh; Kosharskyy, Boleslav; Shaparin, Naum; Gavin, Terrence; LoPachin, Richard M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 357, No. 3, 01.06.2016, p. 476-486.

Research output: Contribution to journalArticle

@article{2699c2c5832e4f1299f7968a8b25c285,
title = "Enolate-forming phloretin pharmacophores: Hepatoprotection in an experimental model of drug-induced toxicity",
abstract = "Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2′,4′,6′-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.",
author = "Geohagen, {Brian C.} and Amaresh Vydyanathan and Boleslav Kosharskyy and Naum Shaparin and Terrence Gavin and LoPachin, {Richard M.}",
year = "2016",
month = "6",
day = "1",
doi = "10.1124/jpet.115.231001",
language = "English (US)",
volume = "357",
pages = "476--486",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Enolate-forming phloretin pharmacophores

T2 - Hepatoprotection in an experimental model of drug-induced toxicity

AU - Geohagen, Brian C.

AU - Vydyanathan, Amaresh

AU - Kosharskyy, Boleslav

AU - Shaparin, Naum

AU - Gavin, Terrence

AU - LoPachin, Richard M.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2′,4′,6′-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.

AB - Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2′,4′,6′-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84975159397&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975159397&partnerID=8YFLogxK

U2 - 10.1124/jpet.115.231001

DO - 10.1124/jpet.115.231001

M3 - Article

VL - 357

SP - 476

EP - 486

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -