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J Pharm Pharmacol. 2017 Dec;69(12):1762-1772. doi: 10.1111/jphp.12812. Epub 2017 Sep 5.

Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies.

Author information

1
Graduate Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
2
Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
3
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.

Abstract

OBJECTIVES:

Excessive exposure to acetaminophen (APAP, paracetamol) can cause liver injury through formation of a reactive metabolite that depletes hepatic glutathione and causes hepatocellular oxidative stress and damage. Generation of this metabolite is mediated by Cytochrome-P450 (CYP) isoforms, mainly CYP2E1. A number of naturally occurring flavonoids can mitigate APAP-induced hepatotoxicity in experimental animal models. Our objective was to determine the mechanism of these protective effects and to evaluate possible human applicability.

METHODS:

Two flavonoids, luteolin and quercetin, were evaluated as potential inhibitors of eight human CYP isoforms, of six UDP-glucuronosyltransferase (UGT) isoforms and of APAP glucuronidation and sulfation. The experimental model was based on in-vitro metabolism by human liver microsomes, using isoform-specific substrates.

KEY FINDINGS:

Luteolin and quercetin inhibited human CYP isoforms to varying degrees, with greatest potency towards CYP1A2 and CYP2C8. However, 50% inhibitory concentrations (IC50 values) were generally in the micromolar range. UGT isoforms were minimally inhibited. Both luteolin and quercetin inhibited APAP sulfation but not glucuronidation.

CONCLUSIONS:

Inhibition of human CYP activity by luteolin and quercetin occurred with IC50 values exceeding customary in-vivo human exposure with tolerable supplemental doses of these compounds. The findings indicate that luteolin and quercetin are not likely to be of clinical value for preventing or treating APAP-induced hepatotoxicity.

KEYWORDS:

CYPs; UDP-glucuronosyltransferase; acetaminophen; drug interactions; flavonoids

PMID:
28872689
PMCID:
PMC6309961
DOI:
10.1111/jphp.12812
[Indexed for MEDLINE]
Free PMC Article

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