Inflammation-associated extracellular beta-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene

Q. Shi, G.R. Haenen, L.M. Maas, V.M. Arlt, D. Spina, Y.R. Vasquez, E. Moonen, C. Veith, F.J. van Schooten, R.W. Godschalk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Neutrophils infiltrate tissues during inflammation, and when activated, they release beta-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular beta-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 beta-glucuronidase. beta-Glucuronidase reduced B[a]P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on beta-glucuronidase activity, because the inhibitor D-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of beta-glucuronidase. On the other hand, the inhibitory effect of beta-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for beta-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of beta-glucuronidase. Extracellular beta-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P-DNA adducts. Interestingly, at 24 h of exposure, beta-glucuronidase significantly enhanced CYP expression, probably because beta-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 beta-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 beta-glucuronidase. Overall, these data show that beta-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels.
Original languageEnglish
Pages (from-to)2261-2273
Number of pages13
JournalArchives of Toxicology
Volume90
Issue number9
DOIs
Publication statusPublished - Sep 2016

Keywords

  • Benzo[a]pyrene
  • Inflammation
  • beta-Glucuronidase
  • Cytochrome P450 1A1
  • Carcinogen metabolism
  • IGF2R
  • DNA adducts
  • BREAST-CANCER CELLS
  • MANNOSE 6-PHOSPHATE-INDEPENDENT ENDOCYTOSIS
  • ARYL-HYDROCARBON RECEPTOR
  • BLOOD-BRAIN-BARRIER
  • DNA ADDUCT LEVELS
  • IN-VIVO
  • UDP-GLUCURONOSYLTRANSFERASES
  • AERODIGESTIVE TRACT
  • NEUTROPHILS
  • METABOLITES

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