Flavin-containing monooxygenase-3: Induction by 3-methylcholanthrene and complex regulation by xenobiotic chemicals in hepatoma cells and mouse liver

Journal Article · Sun Aug 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.05.018· OSTI ID:21460199

Celius, Trine ^[1]; Pansoy, Andrea ^[1]; Matthews, Jason ^[1]

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1. Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8 (Canada)

Flavin-containing monooxygenases often are thought not to be inducible but we recently demonstrated aryl hydrocarbon receptor (AHR)-dependent induction of FMO mRNAs in mouse liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Celius et al., Drug Metab Dispos 36:2499, 2008). We now evaluated FMO induction by other AHR ligands and xenobiotic chemicals in vivo and in mouse Hepa1c1c7 hepatoma cells (Hepa-1). In mouse liver, 3-methylcholanthrene (3MC) induced FMO3 mRNA 8-fold. In Hepa-1 cells, 3MC and benzo[a]pyrene (BaP) induced FMO3 mRNA > 30-fold. Induction by 3MC and BaP was AHR dependent but, surprisingly, the potent AHR agonist, TCDD, did not induce FMO3 mRNA in Hepa-1 cells nor did chromatin immunoprecipitation assays detect recruitment of AHR or ARNT to Fmo3 regulatory elements after exposure to 3MC in liver or in Hepa-1 cells. However, in Hepa-1, 3MC and BaP (but not TCDD) caused recruitment of p53 protein to a p53 response element in the 5'-flanking region of the Fmo3 gene. We tested the possibility that FMO3 induction in Hepa-1 cells might be mediated by Nrf2/anti-oxidant response pathways, but agents known to activate Nrf2 or to induce oxidative stress did not affect FMO3 mRNA levels. The protein synthesis inhibitor, cycloheximide (which causes 'superinduction' of CYP1A1 mRNA in TCDD-treated cells), by itself caused dramatic upregulation (> 300-fold) of FMO3 mRNA in Hepa-1 suggesting that cycloheximide prevents synthesis of a labile protein that suppresses FMO3 expression. Although FMO3 mRNA is highly induced by 3MC or TCDD in mouse liver and in Hepa-1 cells, FMO protein levels and FMO catalytic function showed only modest elevation.

• OSTI ID: 21460199
• Journal Information: Toxicology and Applied Pharmacology, Vol. 247, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.05.018; PII: S0041-008X(10)00191-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
3-METHYLCHOLANTHRENE
CYCLOHEXIMIDE
DIOXIN
HEPATOMAS
LIVER
MICE
OXYGENASES
ANIMALS
ANTIBIOTICS
ANTI-INFECTIVE AGENTS
AROMATICS
BODY
CARCINOMAS
CONDENSED AROMATICS
DIGESTIVE SYSTEM
DISEASES
DRUGS
ENZYMES
FUNGICIDES
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
MAMMALS
NEOPLASMS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
OXIDOREDUCTASES
PESTICIDES
POLYCYCLIC AROMATIC HYDROCARBONS
PROTEINS
RODENTS
VERTEBRATES