title: Inflammation-associated extracellular β-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene.
abstract: Neutrophils infiltrate tissues during inflammation, and when activated, they release β-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular β-glucuronidase changed the in vitro cellular response to the chemical carcinogen benzo(a)pyrene (B[a]P). For this we exposed human liver (HepG2) and lung (A549) cells to B[a]P in the presence or absence of β-glucuronidase. β-Glucuronidase reduced B[a]P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on β-glucuronidase activity, because the inhibitor D-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of β-glucuronidase. On the other hand, the inhibitory effect of β-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for β-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of β-glucuronidase. Extracellular β-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P-DNA adducts. Interestingly, at 24 h of exposure, β-glucuronidase significantly enhanced CYP expression, probably because β-glucuronidase de-glucuronidated B[a]P metabolites, which continued to trigger the aryl hydrocarbon receptor (Ah receptor) and induced expression of CYP1A1 (in both cell lines) and CYP1B1 (in A549 only). Consequently, significantly higher concentrations of B[a]P metabolites and DNA adducts were found in β-glucuronidase-treated cells at 24 h. DNA adduct levels peaked at 48 h in cells that were exposed to B[a]P and treated with β-glucuronidase. Overall, these data show that β-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels.
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Q
authors.identifier: http://orcid.org/0000-0001-8491-9548
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: G R
authors.initials: GR
authors.lastname: Haenen
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Maas
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental and Health, King's College London, 150 Stamford Street, London, SE1 9NH, UK.|NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King's College London in Partnership with Public Health England, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: V M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: D
authors.initials: D
authors.lastname: Spina
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Y Riffo
authors.initials: YR
authors.lastname: Vasquez
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Moonen
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Veith
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: F J
authors.initials: FJ
authors.lastname: Van Schooten
authors.affiliation: Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. r.godschalk@maastrichtuniversity.nl.
authors.forename: R W L
authors.initials: RWL
authors.lastname: Godschalk
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000494:pharmacology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017527:Receptor, IGF Type 2 / Q000819:agonists / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts; D005966:Glucuronidase; D008070:Lipopolysaccharides; D017527:Receptor, IGF Type 2; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C056612:benzo(a)pyrene-DNA adduct; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human
keywords: Benzo[a]pyrene; Carcinogen metabolism; Cytochrome P450 1A1; DNA adducts; IGF2R; Inflammation; β-Glucuronidase